UA61884C2 - 1,3-propane diol derivatives as biologically active compounds - Google Patents

Abstract

Compounds of 1,3-propane diol linked structure (I), when for use in therapy, where R1 is an acyl or fatty alcohol group derived from a C12-30 preferably C16-30 fatty acid desirably with two or more cis or trans double bonds, and R2 is hydrogen, or an acyl or fatty alcohol group as R1 the same or different, or any other nutrient, drug or other bioactive residue.

Description

Description of the invention

This specification refers to the form of implementation of bioactivators; by this term, the authors understand a medicinal product, an essential nutrient, and any other compound that can be introduced into a human or animal body for the purpose of therapeutic intervention or preventive measures. In a narrower sense, this specification refers to: implementation of the mentioned bioactivators in the form in which they are lipophilic, which allows them to easily pass through the lipid barriers of various tissues of the body; or implementation of two bioactivators in the same molecule (where at least one of them is a fatty acid or a fatty alcohol); or 70 implementation of substances of bioactivators in a form that can serve to achieve the two aforementioned goals and/or to facilitate the synthesis of similar compounds without a chiral center. From the point of view of drug stability, it is a great advantage that two bioactivators can represent a common single molecule, compared to their existence in the form of two separate chemical units. There is also an opportunity to implement already known bioactivators in new versions. Advantages include increased lipophilicity, additional additive effects of 12 two bioactivators, which are not found together in conventional formulas, as well as sporadic synergistic effects of such substances.

This invention relates to the chemical combination of bioactivators through certain molecular bonds, a detailed description of which is given below in the text of the document, as well as the synthesis of a number of compounds; some of these compounds are themselves completely novel compounds, while the novelty of others is considered in terms of their utility in therapeutic treatment and/or health maintenance. But there is a controversial question regarding compounds in which other binding molecules are used that are not currently declared, as well as compounds with a direct chemical bond, described, for example, in EPA-O 393 920, in relation to fatty acids and antiviral agents, and in jointly filed EP-95301315.8 (published as EP-0 675 103), regarding fatty acids and non-steroidal anti-inflammatory drugs. with

The concepts considered above were not given much attention in the published patent and general scientific (9) literature, but there are data on some described derivatives of natural diols and on the use of some specific diol esters for nutritional and pharmaceutical purposes. The original publication in the general scientific literature can be considered the article by Vegdeivop (Viospit., Viorpuz. Asia 116 (1966) 511-520), where, in particular, a description of long-chain diesters of 1,3-propanediol is given. In that work, very little information was given about the acidic components of the compounds, but it was determined the very concept of diol derivatives. In the patent literature, data on chemical imitators of edible fats, for example, were proposed by Mabizso in EKA-0 405 873 and EPA-O 405 874; in this work, linolenic acid esters (under this name) were classified as such compounds , when no other specific definition is given, the "alpha" isomer) and arachidonic acid esters are to be understood, apparently 1,4-butanoic "-- diol. In the common British specification 2 161 477 (corresponding to EPA-O 161 114) highlights the growing number and economic importance of pharmaceutical companies that, in particular, use 1,3-propanediol ee, linoleic acid and linolenic acid esters (again, without doubt, alpha- isomer). Anti-ulcer drugs based on 2,3-butanediol ethers are described in ERA-0O 056 189 of the company 55 Раптасециисай Со. Various pharmaceutical effects of propane-1,3-diol esters of short-chain fatty acids are shown in ERA-O 018 342 "of the company Zapoiia. More distant from the topic is the chemical connection of 5-fluoro-uracil with alpha-linolenic acid, with digomo-gamma-linolenic acid, or with eicosapentaenoic acid through the group -CH(K)-O-, where K is methyl c, etc.; these modifications give, in particular, an anti-cancer therapeutic effect. from" Lipid barriers

Many drugs affect the surface of the cell membrane by direct connection with cellular reagents-receptors, or, on the contrary, penetrate into the cell with the help of specific transport 42 systems. On the other hand, there are a number of drugs that cannot effectively penetrate the cell and process it because they act inside the cell by changing only one of many different functions, including the functions of nucleic acids, intracellular enzymes, or by changing the properties of such systems as lysosomes or microtubules. Obviously, there are no such reagents-receptors or transport systems with which similar drugs would be able to chemically bind, or these systems are capable of transporting drugs into the cell too slowly. That is, although such drugs can penetrate deeper intracellular membranes, such as the membranes of mitochondria and nuclei, but this happens too slowly.

T» There are other barriers preventing the movement of drugs that are recognized as important. One of them is the blood-brain barrier, which has a number of similar characteristics compared to the cell membrane. For many drugs, it is impossible to achieve their required concentration in brain tissues precisely because of the presence of the 29 mentioned barrier. Another matter is the effect of the drug on the body through the skin: until recent years

GF) drugs were used in this way only in those cases when the object of treatment was the skin itself. But it is now being recognized that the skin can be a very acceptable "delivery route" for systemic drugs, and as a result, more and more compounds are being manufactured so that they can be administered by patching, etc. 60 All three types of barriers - cell and intracellular membranes, blood-brain barrier and skin covers - have the characteristic common feature that they consist largely of lipids. This means that they are chemically impermeable to drugs created on the basis of aqueous solutions, unless there is a suitable reagent-receptor or transport system capable of escorting these drugs through said membranes.

On the contrary, lipophilic substances are able to pass through barriers quite easily and do not require any specific reagents-receptors or transport systems.

Classes of bioactive compounds that require chemical support in the process of penetrating cells through lipid barriers

Drugs whose pharmacokinetic properties can be improved by increasing lipophilicity are listed according to the principle of the route of delivery to the tissues of the body: 1. Cellular entry: drugs with an intracellular effect have the greatest advantage. They include: a. All anti-inflammatory drugs, steroidal or non-steroidal; b. All cytotoxic drugs used in the control of carcinogenic processes; in. All antiviral drugs; 70 g. All other drugs that can be introduced into cells in order to achieve optimal results, in particular, drugs that affect DNA or RNA, or intracellular enzymes, or secondary transport systems, or microtubules, mitochondria, lysosomes and any other intracellular elements. d. Steroid hormones and other intracellular hormones, such as female sex hormones, /5 progestins, male sex hormones and dehydroepiandrosterone. 2. Blood-brain barrier: the proposed technology will help to improve the transportation in the body of all drugs that affect the central nervous system. The list of such drugs includes all those used in psychiatry; all drugs that are used in the treatment of cerebral infections in any body, or in the treatment of brain cancers; this list also includes all other drugs that affect nerve cells, including antiepileptic drugs and other drugs that treat neurological disorders, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea, etc.

C. Skin: As in the case of the blood-brain barrier, all drugs that need to be administered through the skin to achieve a systemic effect should preferably be converted to fatty acid derivatives. with

Amino acids can be cited as an example. The most interesting among them are, obviously, those that play a significant role in regulating cell functions, as well as those that act as components of proteins. These include i) tryptophan (a precursor of 5-hydroxytryptamine I5-NTI, a key regulator of nerve and muscle function), phenylalanine (a precursor of catecholamines) and arginine (a regulator of nitric oxide synthesis, which also plays a significant role in controlling cellular processes) . General comparison of properties

In general, the compounds of this invention have a number of advantages in addition to their increased lipophilicity. Two component parts of a fatty acid or even one of the components can be introduced into the body in a convenient form both orally and parenterally or superficially; the compound according to the present invention is cell tolerant (without any side effects) with free fatty acids; the compound according to the present invention is not too stable to be completely utilized; the compound according to the present invention does not require the presence of a chiral center; also the compound according to the present invention is much easier to synthesize than corresponding triglyceride with three components of the same fatty acid attached.

Despite the fact that triglycerides are highly tolerated compounds and are well utilized, their use is less practically advantageous than the use of the compounds proposed in the present invention: the fact is that their binding is more difficult, and they must have a chiral center with several potential with isomers. In addition, with triglycerides, fatty acids can relatively easily migrate from one position to another. another, creating new molecules that are not present in the original drug. This obviously creates additional problems, especially in the context of drug stability in cases where instability cannot be tolerated.

When it is necessary to introduce two different fatty acids into the body, the advantages of the compounds of the present invention are obvious,

Ge" plus the possibility of simultaneous appointment of two activators with different biological properties in the form of a single molecular compound. This allows you to avoid problems of a regulatory nature that arise during - the appointment of two substances as separate compounds, as well as to get rid of problems that appear where they are needed

Go! chiral centers of a chemical molecule. When it comes to the supply of two drugs in the form of different compounds, each with its own molecule, representatives of local official pharmaceutical institutions usually require a separate study of both each compound and their joint action. If these two compounds are chemically united under a single molecule, there is a need (dictated by the requirements of official institutions - transl.) to study only that single molecule, which significantly reduces the cost of introducing the drug. Similar advantages are observed in the case when the activators are not are fatty acids. The use of the compounds of the present invention makes it possible to prescribe drugs or other mixtures in the form of non-chiral relatively lipophilic compounds (if those drugs or other compounds are themselves chiral). Thanks to this, the active components can be relatively easily (F, released , and the tolerance of oral, topical or parenteral administration may be improved. Lipophilicity allows such drugs to be partially adsorbed through the lymph nodes, bypassing the liver, and the use of the compounds of this invention also results in a lower risk of gastrointestinal irritation than with many others. compounds; in addition, the use of compounds according to o with this invention facilitates and accelerates the transport of drugs and other agents across such lipophilic barriers as the skin, cell membrane, and blood-brain barrier. It is obvious that for many nutritional and pharmaceutical preparations, in the case of increasing their lipophilicity, many interesting specific properties can be revealed, in addition to easier penetration through lipid barriers. Among such properties can be attributed the prolongation of the action, the reduction of side effects, especially from the gastrointestinal tract, the exclusion of the primary biochemical metabolism in the liver and, in the future,

taking into account the peculiarities of local delivery of various substances.

Derivatives of fatty acids; effects of exposure to fatty acids

The transport of active compounds through lipid membranes can be improved by their direct binding or binding through intermediate links (rings), in particular with gamma-linolenic acid (SI A) or digomo-gamma-linoleic acid (DI A), i.e. two acids, which in themselves are characterized by several beneficial effects. Similar connections also allow the introduction of other bioactive compounds in the form of a single molecule with fatty acids, which are already capable of providing beneficial effects in relation to the effect on the body independently of any advantages associated with the transfer of the substance. Other fatty 7/0 acids can also be used, for example, any of the essential fatty acids (EPA) and, in particular, the twelve natural EPA acids of the n-b and n-3 series (Fig). Of these twelve, arachidonic, adrenoic, stearidonic, eicosapentaenoic, and docosahexaenoic acids are the most interesting because they have desirable effects in their own right. In addition, any fatty acid corresponding to the number of C 15-Czo or C16-Czo carbon atoms can be used, preferably with two or more cis or trans carbon-carbon double bonds. Practical use may be acceptable in the form of a fatty acid or a corresponding fatty alcohol. Conjugated linoleic and columbic acids are an example of fatty acids that have valuable properties in themselves and are obviously of particular interest from the point of view of their practical applications. References to fatty acids in the text of the present invention should refer to both forms, with the exception of those cases when the chemical structure of one or another form has its own specificity and is subject to additional discussion. It should be noted that the practically useful properties of SIA and rogA make them particularly attractive for achieving the goal set by this invention.

Essential fatty acids, which in natural conditions can be represented by all cis-configurations, are systematically assigned the names of derivatives of octadecanoic, eicosanoic, or docosanoic acids, respectively, for example, 27,2-octadeca-9,12-dienoic acid or 7,7,7,7,7 ,2-doCcose-4,7,10,13,16,19-hexaenoic acid, but the numerical numbering is based on the number of carbon atoms, on the number of centers of unsaturation and on the number of carbon atoms at the end of the chemical chain where unsaturation begins, for example, 18:2p-6 or 22:bp-3.

For common chemical names, in some cases, abbreviations are used, for example, EPA, and abbreviated i) forms of the inscription, for example, eicosapentaenoic acid.

SIA tarosiA

By themselves, SIA and OSIA are known as compounds that have anti-inflammatory properties, lower blood pressure, inhibit the accumulation of small lamellar plaques of harmful substances, lower cholesterol, inhibit the development of cancer cells, reduce the impact of dyskinetic (uncoordinated) movements, and soothe pain in the chest, improve the absorption of calcium and facilitate its deposition in bone tissue, reduce the harmful effects of ionizing radiation, treat various mental disorders, promote better stretching of the walls of blood vessels, improve kidney function, treat complications in the course of the disease (/-/87 zv5 On diabetes , in general contribute to the expansion of blood vessels, etc. Thus, active reagents, svazheniz (au

SIA and OSA become not only more lipophilic, improving the properties of penetration through membranes, skin and blood-brain barriers, but, in addition, acquire new therapeutic properties. Therefore, compounds based on fatty acids can be two-way (with a direct connection) or three-way (with the existence of an intermediate connection) interchangeable drugs. "

Other fatty acids that are of particular value in this context include: arachidonic and c-docosahexaenoic acids, which are the main components of all cell membranes; adrenal

And acid; stearidonic and eicosapentaenoic acids, which have a number of practically valuable properties, and? similar to SA and OSI A. Conjugated linoleic acid (siaA) and columbic acid (SA) can be included in the list of the most interesting fatty acids that were not included in Fig. SiA acid has certain interesting properties in the treatment and prevention of cancer, in particular, it activates the increase in volume

He" of protein-containing tissues, helps in the treatment and prevention of cardiovascular diseases and plays an important role as an antioxidant. CA also has most of the beneficial properties of essential fatty acids. - Classes of active substances that effectively interact with bisactive fatty acids o Active medicinal substances that can form compounds with the substances proposed in this invention include a wide range of medical preparations: so a). Preparations containing antibiotics, antiprotozoals (agents against protozoa), antipsychotics, antidepressants, NSAIDs (non-steroidal anti-inflammatory compounds) and compounds used in the treatment of cardiovascular, dermatological, mental, neurological, renal, muscular, gastrointestinal intestinal, cancer diseases, as well as respiratory and reproductive diseases, etc. 5B b). Hormones. in). Amino acids.

F) d). Vitamins, especially group B, as well as other nutritious essential substances. ka d). Cytokines and peptides. is). Neurotransmitters and chemical precursors of neurotransmitters. same).Phospholipid head groups such as inositol, choline, serine and ethanolamine, which can be connected directly to each other or through an intermediate phosphate component. 3). Aromatic fatty acids such as phenylacetic acid, phenylbutyric acid and cinnamic acid, which are of particular importance in the treatment of cancer.

Effectiveness 65 The combination of the therapeutic effect of the drug and the therapeutic effect of the fatty acid can be illustrated by the following examples:

and). Psychotropic drugs can be attached to fatty acids, such as SG A, OO A, arachidonic, eicosapentaenoic or docosahexaenoic acid, which play an essential role in regulating brain function; thus providing a double therapeutic effect. b). Drugs used to treat cardiovascular diseases can be attached to a fatty acid, which itself also has therapeutic value; such acids include: eicosapentaenoic acid, which lowers triglyceride levels and inhibits the accumulation of small plaques of harmful substances, as well as si A or OSI A, which lowers cholesterol levels and contributes to the expansion of blood vessels; this includes arachidonic acid, which is a powerful cholesterol-lowering agent, as well as ONA, 7/0, which has properties that contribute to the disappearance of heart arrhythmia. in). Drugs used in the treatment of inflammatory processes in any form can be attached to the following fatty acids: hamalinolenic, digomo-hamalinolenic, eicosapentaenoic, or to docosahexaenoic acid, which also acts as an anti-inflammatory agent. d). Drugs used to control the development of osteoporosis can be added to 75 ZA or OO A, which increase the calcium content in bone tissue; these drugs can also be attached to

ERA or ONA, which reduce the excretion of calcium in the urine. d). Drugs used in skin diseases can be added to SI A or Obi A, which have an anti-inflammatory effect on the skin. is). Drugs used in oncology can be added to SI A, OSI A, arachidonic acid,

ERA or ONA, which themselves have properties of anticancer agents and, moreover, are able to reverse resistance to other anticancer drugs.

The concept of using essential fatty acids as bioactivators

Essential fatty acids (EPA), as already mentioned in the text of the present invention and well known to specialists, form a series of twelve compounds. Although linoleic acid, the primary (parent) compound of the p-b series, and s-alpha-linolenic acid, the primary acid of the p-3 series, are the main dietary acids, they, as independent substances, have relatively little importance in the body. For their fuller use in body tissues, i) the main compounds must be metabolized into compounds with long-chain molecules and have a greater degree of unsaturation. If it is evaluated quantitatively, paying attention to the real participation of the substance in the chemistry of cell membranes and in other lipid reactions, it should be noted that the main metabolites of ERA of the p-6 series are "gzo digomogamalinolenic (OSI A) and arachidonic (AK) acids, and the main metabolites of ERA of the p-3 series are eicosapentaenoic (EPA) and docosahexaenoic (ONA) acids. UOSIA, AK, ERA and ONA are the most important co-components of most lipids in the body. In addition to the fact that they themselves play an essential role in biochemical processes, they are also the basis for the creation of a wide range of oxidized derivative compounds, eicosanoids, including prostaglandins, leukotrienes, etc. It is obvious that a special role in therapy is played by (87 mentioned OSIA, AK, ERA and ONA, together with SI A - the precursor of EUSIA, stearidonic acid (ZK) - "the precursor of ERA), and ORA (docosapentaenoic acid) (22:51-3 ) - a precursor of ONA, as well as with adrenic acid.

In addition, oleic acid, parinaric acid and niobic acid, which do not belong to EPA, but play an essential role in chemical processes in the body, are successfully used in therapy. One of the most interesting among them is conjugated oleic acid, which, as noted earlier, has a number of useful properties.

And there was an opinion that, both for the purpose of nourishing the body and during therapeutic treatment, the main thing? the moment is the introduction of primary linoleic and alpha-linolenic acids, and the own metabolism of the living organism, they say, will complete the rest of the matter. Now, most experts agree that this is not the case.

Different diseases can be accompanied by different abnormal characteristics of EPA, and because of complex problems with the metabolism itself, these abnormalities cannot be corrected only by the introduction of linoleic or alpha-linolenic acid. Therefore, in many situations there is a need to prescribe larger volumes of one or another ERA, or to introduce two or more ERAs at the same time. Since ERA can be introduced in different

Go! forms and in various mixtures, both for the purpose of nourishing the body and for therapeutic purposes, it is convenient to have

Ability to introduce fatty acids as substances with separate molecules. Also, in various situations, it is desirable to co-introduce EPA or another fatty acid into the body together with an amino acid, vitamin, any drug and other substances that have beneficial properties in themselves. Until recently, proposals for the appointment of two fatty acids at the same time mainly concerned triglycerides, taking into account the natural form of existence of essential fatty acids in the form of triglycerides. However, if modifications with symmetry about the 2g-carbon are not taken into account, triglycerides are compounds with chiral centers, and this, together with the migration of the acidic residue (acyl) between the alpha and beta positions, makes the synthesis of specific triglycerides a difficult task. The mentioned (F, migration can create certain problems after the synthesis from the point of view of the regulatory aspect of the use of the drug. The lack of specificity of the effect, when two fatty acids are present in one triglyceride molecule, causes many difficulties from the point of view of synthesis, pharmacology, development and preservation of stability compounds. In addition, the actual synthesis of triglycerides can be slow and difficult. Under the same starting conditions, propanediol derivatives can be produced much faster. In order to facilitate the simultaneous administration of different fatty acids or the administration of a true single fatty acid in large doses and in a well-tolerated form, the authors recommend giving preference to the use of diol ethers (ethylene glycols).

Chemical nature of bioactivators whose derivatives are offered according to the present invention 65 This specification covers fatty acid (or fatty alcohol) derivatives, which refer to substances with a carboxyl, alcohol or amino group, which are chemical units with a single, well-defined formula. The chemical connection can be carried out by direct connection of mobile groups of two-component compounds or through a corresponding intermediate binding group, in the case of three-component compounds, depending on the number of component parts into which the mentioned compounds are decomposed.

Chemical classification of the proposed bioactivators

Further, the text provides classes of compounds for which n varies from 1 to 3. This invention claims such compounds included in the diesters of class (a) (iii); n-3. This invention also claims phosphate esters of class (b) (m); n-3. Substances where n is a white or smaller number, or in which the chemical bonds are not of the ether type of bonds, may also be valuable compounds for similar reasons and are already disclosed, but are not discussed in detail in this invention. and not formulated. (a) Bioactivators with a free carboxyl group - derivatization can occur as follows: (І) ether connection with an unsaturated fatty alcohol (REA): рій гу

Bisactivator t zi ad I : : : « is . (i) an ether bond with an o-hydroalkyl ether of an unsaturated fatty acid: о 8) ра А с о 8) о

Pop bioactivator! . ! ! | "(ii) ether bond with 5-hydroalkylcarboxyester of saturated fatty alcohol: (o; (se) p (ee) o id z5 | Bioactivator (Se) (b) Bioactivators with a free hydroxyl group - derivatization can occur as follows: " 20 (Ж) ether connection with an unsaturated fatty acid: with g» V

Bioactivator o (o) -3z (ii) ether bond with 5-carboxyalkylcarboxyester of unsaturated fatty alcohol: so o still kO bo 70 | Bioactivator in; o c" (iii) ether bond with "5-carboxyalkyl ether of an unsaturated fatty acid: c)

F) - A yu sha

Bioactivator (o; 60 (im) phosphate ester bond with o5-hydroxyalkyl ester of unsaturated fatty acid: b5

Yi sha Day

Bioactivator | p ok o

CC: H, CH3, or a cationic counterion 70 (c) Bioactivators with a free amino group - derivatization can occur as follows: (Y) amide bond with an essential fatty acid:

N

75 | Bioactivator and

Iv) (i) amide bond with an o-carboxyalkylcarboxyester of an ether fatty acid:

N g

Bioactivator и (9) о с (8) (ии) amide bond with о-carboxyalkyl ester of essential fatty acid: о щу з

With comrades) with

Bioactivator so "-

In all the categories listed above, where H varies from 1 to 3, the carbon-containing chain of the ith unsaturated fatty acid or alcohol is represented: х т0 c ORGA) is a member of the group containing oleic acid (and oleoyl alcohol) and any c" fatty acid (or corresponding fatty alcohol) with two or more cis or trans double bonds. But it should be noted that essential fatty acids, which are preferred in the context of the present invention, are exactly those acids shown in the figure, especially SI A, OSI A, AK, ERA and ONA. In some cases, there may be an interest in the use of conjugated linoleic and columbic acids.

Ф General description of the synthesis - Fatty acids in their own form can be isolated from natural animal, vegetable and microbiological matter or can be chemically synthesized using methods known to specialists, or with the methods proposed later in this document. (oo) 20 Fatty alcohols in their own form can be produced by chemical reduction of the mentioned fatty acids also using methods known to specialists, or methods proposed further in this

T" documents.

Derivatization (production of chemical derivatives) of bioactive compounds of classes (a), (b) and (c) (subclasses (ii) and (NI)) requires the formation of one or more ether bonds. 25 Such chemistry can be carried out using any optimal method of synthesizing ethers, in particular:

HF) (a) by reaction of an alcohol with an acid chloride, an acid anhydride or a correspondingly activated ether in the presence (or without) of an organic tertiary amine (for example, pyridine), in a suitable inert solvent (for example, dichloromethane), at a temperature from 0" to 12076. (b) by reacting an alcohol with an acid, or with a short- or medium-chain alkyl ester of an acid, in the presence of a suitable acid catalyst (e.g. 4-toluenesulfonic acid), with a suitable inert solvent, e.g. toluene (or without it) , at a temperature from 50" to 1807C, with the condition of complete removal of water formed during the reaction, for example, under vacuum. (c) by reacting an alcohol with an acid in the presence of a condensing agent, for example, 1,3-dicyclohexylcarbodiimide, in the presence (or without) of a suitable organic tertiary amine, for example, 4-(M,M-dimethylaminopyridine), in an inert solvent, e.g., dichloromethane, at a temperature of 0" to 507. (g) by reacting the alcohol with an acid or with a short- or medium-chain alkyl ester of an acid or an activated ester of an acid, e.g., vinyl, in the presence of a hydrolase enzyme, e.g., an etherase taken from the liver of an ungulate of the same age, in the presence (or without it) of a suitable solvent, for example, hexane, at a temperature from 207 to 807"C with the condition of complete removal of reaction by-products, such as water, secondary alcohol and aldehyde, for example, under vacuum. (e) by reacting an acid with a suitable alcohol derivative, for example, an iodide, in the presence (or without) of a suitable base, for example, potassium carbonate, in a suitable solvent, for example, dimethylformamide, 7/0 at a temperature from 0" to 1807C. ( e) by the reaction of an alcohol with a short- or medium-chain alkyl ether of an acid, in the presence of a catalytic volume of an alkoxide of the M'OU" type, where M is an alkali or alkaline earth metal, for example, sodium, and U is an alkyl group containing 1 -4 carbon atoms and can be branched, unbranched, saturated or unsaturated, in the presence (or without) of a suitable solvent, for example, toluene, at 75 temperatures from 507 to 1807C, with the condition that the lower alcohol with the general formula NOM is completely removed from the reaction mixture, for example, under vacuum.

Derivatization of bioactive compounds of class (c) requires the formation of an amide bond. Such chemistry can be realized using an optimal technique for synthesizing amides, in particular: (g) by reacting an amine with an acid chloride, an acid anhydride, or an appropriately activated ether in the presence (or without) of an organic tertiary amine, e.g., pyridine, in a suitable inert solvent , e.g., dichloromethane, at a temperature of 0" to 12076. (3) by reacting the amine with an acid in the presence of a condensing agent, e.g., 1,3-dicyclohexylcarbodiimide, in the presence (or without) of a suitable tertiary amine, e.g., 4-( (M,M-dimethylaminopyridine), in a suitable solvent, for example, dichloromethane, at a temperature from 0" to 90°C. in the presence of a hydrolase enzyme, for example, etherase taken from the liver of an ungulate of the same age, in a suitable solvent (or without it), for example, in xane, at temperatures from 207 to 807 C with the condition of complete removal of by-products of the reaction, such as water, "And alcohol or aldehyde, for example, under vacuum.

Derivatization of bioactive compounds of class (b) (im) requires the formation of complex phosphate-ester bonds. co

Such chemistry can be carried out using any optimal method of synthesizing complex phosphate ethers, in particular: by reacting an alcohol (for example, OBRA, 3-hydroxypropyl ether) with a correspondingly activated phosphate derivative (for example, ROSI»z), with with a tertiary amine (e.g., EIZzM) in a suitable solvent "o (e.g., TNE), at a temperature lower than 10"C, with the yield of crude phosphorodichloridate. The next step should be the reaction of an alcohol (e.g., A-tocopherol) with crude phosphorodichloridate, with with a tertiary amine (e.g., EBM) in a suitable solvent (e.g., tetrahydro-2,5-furandimethanol) at ambient temperature to yield crude phosphorodichloridate. It must be hydrolyzed (e.g., by adding water and E(3M), with As a variant, the addition of methanol 8s leads to the release of a complex phosphotriester, which must be deprived of the methyl group with the help of a suitable nucleophilic substance (for example , lithium bromide), in a suitable solvent (for example, methyl "» ethyl ketone), with the output of a complex phosphodiester. (l) by reaction of a phosphomonoester (for example, OBRA phosphate, 3-hydroxypropyl ether) with an alcohol (for example, choline), in the presence of a condensing agent (for example, 1,3-dicyclohexylcarbodiimide) In

Ge") to the appropriate solvent at the appropriate temperature. with (m) by the reaction of transphosphatidylation of deoxy-2-lysophosphatidylcholine with a primary or secondary alcohol, catalyzed by phospholipase Yu. (ee) In general, the chemistry of the drug manufacturing cycle depends on the nature of the compounds that need to be chemically

Connect, and whether these connections are direct or indirect. For example, pairs of fatty acids can be directly connected in the form of esters of a fatty acid-fatty alcohol tandem, or as

Chl» anhydrides, and, if diol binders are used, ether linkages with fatty alcohols are an alternative to the more traditional (usual) ether linkages with fatty acids; in all cases, binding can be carried out using known chemical reactions.

Examples of pairs of active compounds that can be chemically linked directly or through intermediate binding elements, in particular through a 1,3-Propane-diol linker

F. To the extent that it is known to the authors of the invention, the pairs of compounds given below in the text, as well as the resulting co-compounds, are fundamentally new drugs. Therefore, they should be considered, according to one of the aspects of the present invention, as new chemical structures that contribute to new methods of treatment and prevention of diseases, regardless of whether they have been applied for as chemical compounds until now.

Fatty acids

SIGA-OA (OA - oleic acid), SI A-SI A, ERA-ERA, SGA-ERA, SI A-ONA, AK-ONA, AK-ERA, SI A-AK,

SI A-5K, BK-ONA, AK-5K, OSI A-AXIS A, OSI A-SI A, OSI A-5K, OSI A-AK, OSI A-ERA, OSI A-ONA, AK-AK, ERA -5K,

ERA-ONA, ONA-ONA, si A-sI A, si A-SIG A, si A-OSIA, si A-AK, si A-ZK, si A-ERA, si A-ONA, SA-SA, SA -OGA, 65 SA-OSIA, SA-AK, SA-ERA, SA-ONA.

Vitamins

SI A-niacin, SI A-retinoic acid, SI A-retinol, SI A-pyridoxal, Di-Si A-pyridoxine, di-Oi A-pyridoxal and in general any of the acids SI A, OO A, AK, ZK, ERA or ONA with any vitamin containing absorbable acid, vitamin Y and its derivatives and analogues, vitamin E and its derivatives and analogues, vitamin K and its derivatives and analogues, vitamin Wu (thiamine), vitamin Vo (riboflavin), folic acid and pterins related to it, vitamin B", biotin and pantothenic acid.

Amino acids

SI A-tryptophan, SI A-proline, SI A-arginine, SI A- or ONA-phenylalanine, SI A-GABA (aminobutyric acid),

SI A-aminolevulinic acid and generally any acid between SI A, OSI A, AK, ZK, ERA or ONA with any 7/0 naturally occurring amino acid or chemically related compound, for example, taurine and carnitine.

Aromatic acids

SI A-phenylbutyric acid, SI A-phenylacetic acid, SI A-trans-cinnamic acid and in general any of the acids SI A, OSI A, AK, ZK, ERA or ONA with any acid of the arylalkane and arylalkene groups.

Steroids

SI A-hydrocortisone, SI A-estradiol, SI A- and ONA-dehydroepiandrosterone and in general any SA, OSI A, AK,

ZK, ERA or ONA with any natural or synthetic steroid such as estogen, any progestin, adrenal steroid and any anti-inflammatory steroid including betamethasone, prednisone, prednisone, triamcinolone, budesonide, clobetasol, beclomethasone and other related steroids.

Antioxidants

SI A-lipoic acid, UONA-lipoic acid, Si A-tocopherol, di-Si A-3,3'-thiodipropionic acid and in general any of the acids ZA, USIA, AK, 5K, ERA or ONA from any any natural or synthetic antioxidant with which the chemical connection of the indicated acids is possible. The list of such substances includes phenolic antioxidants (for example, eugenol, carnosic acid, caffeic (coffee) acid, BNT, gallic acid, tocopherols, tocotrienols and flavonoid (aromatic) antioxidants (for example, myrecitin, fisetin), polyenes (for example, retinoic acid), unsaturated sterols (e.g. l?-avenosterol), organosulfur compounds (i9) (e.g. allicin), terpenes (e.g. geraniol, abietic acid) and amino acid antioxidants (e.g. cysteine, carnosine).

Preparations "I

SIAs and indomethacin, ibuprofen, fluoxetine, ampicillin, penicillin M, sulindac, salicylic acid, metronidazole, fluphenazine, dapsone, tranylcypromine, acetylcarnitine, haloperidol, mepacrine, chloroquine, co-penicillin, tetracycline, pravastatin, bisphosphonates eg ephedronic acid, pamidronic acid and o chlordronic acid and their sodium salts, adenosyl succinate and adenylosuccinate and related compounds and reagents used as radiopaque substances, as well as generally any of the acids SGA, OSI A, AA, --

ZK, ERA or ONA with any drug, in particular those used in the treatment of infectious diseases, inflammatory processes, including various forms of arthritis, cancer, cardiovascular, respiratory, dermatological, mental, neurological, muscular, kidney, gastrointestinal diseases, as well as diseases of the reproductive system, etc. "

The concept of MZAIIIO drugs; efficiency argumentation

As a specific detailed example of the implementation of the author's concept, variants of various derivatives of non-steroidal anti-inflammatory drugs (M5AIU) and in particular Ci A-ester of indomethacin are proposed. Indomethacin, as well as an anti-inflammatory drug, obviously has an intramolecular effect on the body due to "" inhibition of enzymatic (enzymatic) oxygenase, which converts arachidonic acid into prostaglandin metabolites, which cause the spread of the inflammatory process.

It is known that indomethacin penetrates the cell very poorly, and because of this, it must be prescribed in relatively large doses, which creates a lot of side effects; to compare the cell-penetrating properties of pure indomethacin and indomethacin-SI A, a normal spectral cell line, a breast cancer cell line, and a malignant melanoma cell line were studied. (ee) The results were reported in EPA 0 675 103, where it is shown that in all indicated cell lines the intracellular level of free indomethacin after incubation with it is very low and mostly observed in trace concentrations. On the contrary, if we also consider all the listed cell lines,

Chl» incubation with bound indomethacin-SI A led to accumulation in cells of both indomethacin-Oi A and free indomethicin in very significant concentrations. These results clearly indicate that the CI A ester of indomethacin has the property of effectively penetrating into the cell of the body, after which this compound is de-esterified in the middle of the cell with the release of free indomethacin, and also that, from the point of view of the presence of many common features between cell-membrane, blood-brain and skin lipid barriers,

F, the use of (and A-indomethacin) will contribute to the penetration of indomethacin through the barriers of the last two specified types as well. Similar penetration into the cell and subsequent reverse breakdown into free (unbound) active compounds can be expected for all compounds of the present invention. Aspects of the present invention are set forth in the section entitled "Formula of the Invention" below. The main aspect relates to compounds used for therapeutic purposes where the 1,3-propanediol residue forms a bond between the residues B", 2, B! is a group acyl or fatty alcohol, which is a derivative of a fatty acid with the number of carbon atoms С12.3о, preferably Sib.zo, preferably with two or more cis- or trans-double bonds, and B? is hydrogen, as well as the bond between acyl or a fatty acid group, where B can be a similar or different B group, or another nutrient, or a drug, or another bioactive residue.

In general, these compounds are acid-functional substances esterified directly to the diol residue, but, for example, in a variant with a fatty alcohol or another hydroxide-functional substance,

An intermediate phosphate, succinate or other difunctional acid group should be inserted between KI and/or PB2 and the 1,3-propane-diol residue, especially in those cases where B? is a nutrient, drug, or other bioactive compound with hydroxy or amino functions.

Below in the text, this invention is discussed in a broader aspect, covering a wide range of active substances that have the property of being released in the body.

Since the direct connections of bioactive substances and fatty acids (classes (a), 70 (6) and (c)) have already been discussed previously, this invention relates primarily to class (ai, n - Z, by means of which bioactivators, which are fatty acids in themselves, are joined to fatty acids as diesters of 1,3-propane-diol, as well as class (6ХЎМ), n - 3, by which bioactivators, which are fatty alcohols in themselves or

C-hydroxypropyl ethers are attached to the fatty acid monoester of 1,3-propanediol through a phosphate bond. This diol can be considered as 2-deoxyglycerol with corresponding diesters such as 2-deoxy-1,3-diglycerides. Compounds of class (6bChem), p-C are also based on 1,3-propane-diol and can be considered as 2-dioxy-2-lysophospholipids. Almost all of the compounds listed here are new chemical units, or at least have never been used in human or animal medicine. As a connecting link in the chemical compounds of the diol according to this invention, it is quite often mentioned among other diols in the scientific literature, but the authors are convinced that its use in therapy in the form of an ether fatty acid diester or in the form of a compound with an ether fatty acid - with on the one hand, and as a bioactivator (which is not an essential fatty acid) - on the other hand, has not yet been discovered and should be of special importance. | indeed, it creates favorable conditions for the introduction of a single fatty acid in the form of a complex monoester or diester, if the situation requires the appointment of a fully defined compound; this becomes possible because, according to this invention, the diol, firstly, does not have a chiral center, which, on the contrary, is present in complex glycerol-1(3)-monoesters of SM and in diglycerides (A, B and 1,3 , where the fatty acid in position 1 differs from that in position 3), and, (5) secondly, there are no so-called positional isomers in it. In addition, regardless of the introduction of individual acids, such complex mono- and diesters can be of value in pharmaceutical formulation as emulsifiers. 1,3-propanediol is structurally very similar to the glycerol of natural triglycerides and is an effective system that can be easily and safely introduced into the body. In addition, this invention allows "a rather simple synthesis of the corresponding compounds without problems with the migration of the acyl group, which, in contrast, exist for triglycerides, and without complications associated with optical isomers." The authors, in particular, showed that intravenous infusion and oral administration of an emulsion of complex 1,3-propane-diol diester CO

SI A/ERA lead to a very rapid release of ip past chemically unbound OSI A and ERA and to further - metabolism of CA in AA and ERA in ONA. Similarly, it is shown that complex diesters SI A-OG A and ERA-ERA and complex esters of niacin-SI A and indomethacin-b! And they can also be effectively used by oral (Se) administration with subsequent release of their active biochemical components from the body.

In addition to the above information, in the opinion of the authors, all the 1,3-propanediol derivatives mentioned on pages 26, 27, 28 and 29 are new compounds that have never been described before. Specific diols of fatty acids from those listed in that list, as well as diols in which - on the one hand - there is a fatty acid from the series OSIA, CA, AA, 5K, ERA, ONA, SIA and CA, and on the other - a vitamin, an amino acid, an aromatic acid, a steroid, an antioxidant, or another therapeutic drug are new substances. The range of possible applications of complex diesters of fatty acids is quite wide, they can be used as pharmaceutical agents for the treatment or prevention of diseases in which deviations in the body's fatty acid chemistry have been detected. These compounds can be added to food products or used as nutritional supplements for all patients whose body needs certain fatty acids for the treatment or (22) prevention of diseases. They can also be used as food additives and medicines for animals. In addition, these substances are a good pharmaceutical agent for maintaining healthy skin. The advantages and various specific favorable aspects of the use of drugs according to the present invention can be briefly stated as follows: (ee) (Й) Convenient and safe ways of introducing into the body (for the purpose of therapeutic treatment or nutrition) such 50 drugs as one or two components of unsaturated fatty acids, or one unsaturated fatty acid and one non-fatty acid bioactive compound.

I" (i) The presence of a derivative of a bioactivator, which must be chemically passed through the lipid membranes of living tissues in order to achieve a more effective effect on the body, regardless of the type of lipid barrier (cell membrane, skin or blood-brain barrier); this derivative can have the mentioned useful properties due to the presence of a 1,3-propane-diol addition to an ether fatty acid from the natural series p-6b or p-3, or especially SI A or OSI A, AA, ZK, ERA or ONA, or to of conjugated fatty acids with A or C A. (its) Fatty acid derivative in the composition of the drug, which allows to complement the effective properties of the mentioned drug and fatty acid. (m) Techniques for improving drug transport through lipid barriers of living tissues; this improvement is due to the convenience of the drug's prescription forms mentioned above. (M) The method of producing drugs of increased therapeutic value, which consists in better passage of the drug through the lipid membranes of living tissues; this technique is characterized by the introduction of the drug of the present invention into the composition of medicines. (mi) A method of producing medicaments designed to provide living tissues with one or two of the 65 fatty acids from the list under item (ii), or to provide living tissues with one of those fatty acids associated with another active agent.

Examples of the names of specific compounds were given above in the text of the present invention; examples of synthesis procedures will be provided later in the text.

Effectiveness and application

Information about the specific use of specific groups of compounds can be presented in different parts of the text of the present invention, but the general provisions about the usefulness of complex 1,3-propane-diols are summarized in the following points: 1. Increasing the pharmaceutical tolerance of fatty acids. Leaving triglycerides aside, most of the forms in which fatty acids can be prescribed, including free acids, salts, diethyl ethers, and other glycerides, cause some gastrointestinal intolerance (nausea, vomiting, intestinal upset). The study of complex propane-diol diesters on animals - rats and mice - gave exceptionally good results regarding tolerance. For example, diesters SI A-OG A and SI A-ERA were given to rats and mice in doses up to 10 g/kg body weight, after which no signs of gastrointestinal tract disorders were detected. This shows that the use of diesters is a completely acceptable method of delivering biologically active fatty acids to living tissues. 2. Reduction of drug toxicity. Nonsteroidal anti-inflammatory drugs, such as aspirin and indomethacin, have a bad reputation because of their gastrointestinal toxicity and adverse effects on the walls of the stomach and intestines and bleeding into the digestive tract. Fasted rats were given doses of indomethacin known to cause gastrointestinal damage (5-ZOmg/kg body weight) as free indomethacin; at the same time, the same volume of indomethacin was given in the complex 1,3-propanediol diester with IA. After 24 hours, the animals were killed and dissected to examine the entire gastrointestinal tract for damage. If in the bodies of animals that were given only pure indomethacin, intense damage to the digestive tract was found, then in the group of rats that were given

SI A-indomethacin, almost no damage was found.

C. Efficiency of delivery to tissues of biologically active form of fatty acid. CI A was prescribed in the form of sch dv I A-OIGA or SI A-ERA, and ERA was prescribed in the form SIA-ERA or ERA-ERA. Complex esters were given to experimental animals either orally or intravenously in the form of 2095 emulsion, using as i) an emulsifier oat galactolipid in doses from 0.1 to 2.0 g/kg of weight. Accordingly, after 1, 2, 4, 8 and 24 hours, the animals were killed and plasma, red blood cells and liver tissue were collected. The presence of non-metabolized complex diesters was determined by liquid chromatography with programmed high pressure. The presence of fatty acids (as derivatives of these complex esters) and metabolites of these fatty acids was established by extracting lipids from liver tissue, plasma and red blood cells, with subsequent separation of the obtained lipid fraction into triglycerides, phospholipids, cholesterol esters and free fatty acids. by means of thin-layer chromatography, methylation of fatty acids derived from the mentioned separated fractions, and subsequent analysis of the obtained fatty acids by well-known (87 zv) standard gas chromatography methods. These experiments showed that about 1095 orally administered He complex diester was detected in in the form of complex diester residues. Most of the volume of SI A and EPA was found in the form of free fatty acid or phospholipid and less - in the form of cholesterol ester and triglyceride fractions. Moreover, it was in the phospholipid fractions that a significant part of the total volume could be seen metabolites of SG A, CO A and arachidonic acid, as well as metabolites of EPA, docosapentaenoic acid and "

ONA These studies proved that the complex diester is a source of fairly easy release of fatty acids, which are subsequently metabolized into biologically active substances. Similar results were obtained after of intravenous administration, except that after 1 hour about 4095 complex diester a remained in the primary form, and pure fatty acids were released, metabolized and combined into other lipid fractions during the next 24 hours. It is likely that the unchanged diester forms are biologically active substances in themselves. Linoleic acid in the form of 1,3-diglyceride has been found to be anti-cancer

Ge" effect, which has a targeted effect only on cancerous tissues, but not on normal healthy cells. Such an effect was not observed for other forms of linoleic acid (A. Maivigaki ei ai, Sapseg Kev. 1989; 49: 5702-7). It is possible - to make an assumption that this effect, together with possible other effects, determines the need for introduction

Go! of two fatty acid molecules structurally arranged in the form of 1,3-diglyceride. This molecular arrangement is made possible by the addition of 1,3-propanediol; hence it can be assumed that there is a special sense in the intravenous administration of some of the propane-diol derivatives in order to ensure the circulation of these diol forms in the blood for a certain time before reaching their complete metabolism.

Fatty acids are characterized by a number of biologically and therapeutically useful properties, the detailed description of which is laid out in numerous publications, the authors of which are the inventors and other specialists. The largest two part of the total spectrum of beneficial effects belongs to four fatty acids: IA, OSI A, ZK and EPA.

These effects are considered to be:

F) 1. Effect on the cardiovascular system, including stretching (increasing the elasticity) of vessel walls, lowering blood pressure, inhibiting the accumulation of small plaques of harmful substances, lowering the levels of triglycerides and I 0 -cholesterol, increasing the levels of NOI -cholesterol and inhibiting the growth of smooth muscles is due to neoplasms (that is, proliferation). 2. Anti-inflammatory effects, including reducing the number of pro-inflammatory mediators such as cytokines; thanks to eicosanoids, which are derivatives of arachidonic acid, there is an effect of reducing the influence of neutrophil migration and the probability of respiratory failure caused by neutrophil migration, reducing the strength of local inflammatory reactions, inhibiting inflammation observed in various animal 65 models, for example, inflammation caused by the release of uric acid, and accompanying arthritis; treatment of various inflammatory disorders and complications such as osteoarthritis and rheumatoid arthritis.

3. Immunomodulatory functions, including suppression of excessive immune and allergic reactions in animal models, such as experimental allergic encephalomyelitis and uveitis, increased bronchial and skin reactivity in artificially excited to a sensitive state of animal organisms; animal models also give rise to the concept of the importance of immunomodulatory functions in the treatment of sick humans when an excessive immune response occurs. 4. The function of supporting the respiratory system, including the process of improving the elasticity of the bronchi and inhibiting the process of compression (tightening) of the bronchi. 5. Improving the calcium balance, i.e. increasing the body's ability to absorb calcium, reducing the effect of "washing out" calcium, promoting more active calcium deposition in bones, reducing the local effect of calcium deposition in tissues such as arteries and kidneys. 6. Anti-cancer effects of three types: selective cytotoxic damage and induction of apoptosis only in cancer cells, but not in healthy ones; inhibition of the growth of cancer cells due to quenching the activity of growth factors and suppressing interaction with the secondary transport system, which is responsible for the development of malignant 7/5 Cells; inhibition of the process of the spread of metastases using a mechanism that contributes to a more pronounced effect

E-cadherins, and inhibition of proteolytic enzymes (ezymes) such as urokinases, lipoxygenases, and matrix metalloproteinases, as well as inhibition of cancer-induced wasting (cachexia). 7. Effect on nerve cells, including prevention of normal structure and functioning of nerve cell membrane, as well as normal pre- and postsynaptic functioning of neurotransmitters.

These practically important properties mean that this group of fatty acids can be used in the treatment of various diseases, including cardiovascular diseases of various types; inflammatory processes, including rheumatoid arthritis, osteoarthritis, ulcerative colitis and Crohn's disease; respiratory diseases, in particular asthma; mental disorders, including schizophrenia, alcoholism, distracted attention, depression and illness

Alzheimer's; neurological diseases, in particular multiple sclerosis and Huntington's chorea; diseases of the kidney and urinary tract, in particular, various types of inflammatory processes in the kidneys and the deposition of calcium stones in the urinary tract; disorder in metabolic processes, in particular osteoporosis and excessive local i) deposition of calcium, inflammation and ulcers in the gastrointestinal tract. Despite the fact that conjugated linoleic acid (CLA) has not been tested to the same extent as, for example, SG A or EPA, it is apparently also characterized by a wide range of beneficial properties, particularly important in the treatment of cancer, "E zo cardio -vascular diseases and disorders in the system responsible for metabolism. SI A, OSI A, AA, and niobic acid have beneficial properties for the skin and may be particularly useful in the treatment of skin conditions such as atopic eczema, psoriasis, urticaria, and allergic reactions. co

AA is quite often considered a potentially harmful fatty acid. But it is an important component of all normal types of membranes, and it was found that its concentration significantly decreases during the course of such diseases as atopic eczema, schizophrenia (Noggobip ei aii, Zspihorpgepia Kev. 1994; 13: 195-207) and " about diseases of the cardiovascular system (Noitobip, Rgozviadiapaipz IgeiKoig. ERAzv-Ester fatty acids - ERA - transl. | 1995; 53: 385-96). AA can obviously be considered as an important compound in the treatment of such processes, as well as other mental illnesses, such as alcoholism and distracted attention, in which, in many cases, a low concentration of this substance in the body has been noted. ONA shares some of the specified properties of EPA, but "it should be noted that in a particularly high concentration ONA was detected in cell membranes and, in particular, in pl") with the membranes of heart cells, the retina (eye) and in the membranes of brain cells. SHE is also powerful. anti-inflammatory, and has a positive effect on the cardiovascular system. It is obvious that ONA is a particularly valuable drug for the treatment of cardiovascular diseases, retinal disorders and vision disorders, in particular changes in retinal pigmentation, age-related macular degeneration and dyslexia, as well as mental and neurological disorders, in particular schizophrenia, distracted attention, depression , alcoholism, Alzheimer's disease and

Other forms of dementia and multiple sclerosis.

The latest data indicate that the course of infectious diseases also depends on the presence and content of fatty acids in the body, especially the infection is sensitive to OA, ERA and ONA. Many bacteria die due to the influence of these

Go! fatty acids, in particular bacteria of hereditary infections, which are highly resistant to antibiotics. 5r The results of research in many laboratories also indicate the importance of these fatty acids for the successful fight against diseases such as malaria and protozoal diseases. Thus, there is no doubt about the conclusion that various specific fatty acids can be added to enhance the effectiveness of drugs and bioactive substances of almost every class used both for the treatment and prevention of diseases, for the preservation of the skin and for ov Nutrition of the body; they are also of great therapeutic value when administered in the form of diols, either as a single fatty acid or as two different fatty acids in the same molecular structure. Huge

F) the importance for therapy is that in most cases fatty acids are non-toxic substances and they can be prescribed in large doses without any risk of significant side effects.

The following testing can be cited as a concrete example of the therapeutic effectiveness of complex diesters. 1,3 bo I A-ERA propane-diol-diether was tested for the treatment of human pancreatic cancer (AZRO-1), which was transplanted subcutaneously into nude mice capable of accepting external transplants without rejection due to the loss of goiter function. Each of 15 mice was injected subcutaneously with 5 million

AZRO-1 cancer cells prepared as a suspension in Matrigel and OMEM buffer. A malignant tumor developed in the body of each animal, the size of which was determined with the help of calipers, and its volume was estimated by 65 linear measurements. Tumors in each animal were measured twice a week for five weeks. The mice were divided into three groups. 5 animals were used as controls; they were only given 10 g/kg of grain oil daily. The other 5 animals were also given 10 g/kg of grain oil, but in addition, two injections per week of complex diester SG A-ERA were given at the rate of 1.5 g/kg of weight for each injection. This diester was introduced in the form of 2095 emulsion, where the emulsifier was oat galactolipid 296; the tolerance of the intravenous emulsion was very good, which completely excluded the possibility of hemolysis, thrombophlebitis or any similar malaise in the animals. 5 mice of the third group were given 10 g/kg of weight/day of the same SI A-ERA diester instead of grain oil. This experimental treatment lasted for three weeks, after which the tumors continued to grow for another two weeks before the mice were killed and the tumors excised and weighed. The weight of the excised tumor tissue was as follows: in the control group - 1240 - 290 mg; in the intravenous injection group 70. ZIA-ERA - 820 x 180 mg; in the group of oral administration of SIGA-ERA - 490 x 160 mg. It can be seen from this that both oral and intravenous administration of diefer SG A-ERA lead to a significant inhibition of tumor development without any side effect or malaise among the experimental animals. This proves the effectiveness of the use of SG A-EPA diester in the treatment of cancer, which was predicted by the results of experiments in laboratory conditions, when OA and EPA were examined separately for their independent ability to kill cultured human 7/5 cancer cells. Thus, it should be noted that diesters are biologically active agents when different fatty acids are prescribed. Therefore, it can be hoped that many practical beneficial properties of fatty acids will be realized thanks to diesters, which have been described in numerous publications in the scientific literature (for example, Nogtobip OB, ed., Oteda-b Ezzepiiai Ratsu Asidv: Ra(porpuzioiyudu apa Koievz ip Siipisa! Measippe:

UMieu-Yi ivv, Mem/ ZhMogkK, 1990. bBitorocioz AR ei aiY, Neayi EPesiv oi Oteda-3 Roiushpzaishigaiei Ratsu Asiaz ip Zeatyuodz, Kagdeg, Vazei, 1991. Raiv apa Ov ip Nytap Mitiop, Muopa Neakp Ogodapigayop, Kote, 1994.

OpzaiSgabea Rayu Asidv: Miigiopa!i apa RvNuvzioiodisa! Zidpiysapse Vgyivy Miyiop Rotsipaayop, Spartap apa

Nai, Gopaop, 1992).

The specifics of the use of individual 1,3-propane-diol compounds 1. 1,3-propane-diol as derivatives containing: two fatty acids, of which one fatty acid is SI A or c

OA, and the other is CHA, OSHA, ZK, ERA, ONA, CHA (conjugated linoleic acid) or CA (niobic acid); are used to treat: o (a) complications of diabetes, in particular pathologies of the nervous system and retina; also to improve the response to insulin in diabetes and in the previous period; (b) cancer diseases; "And (c) osteoarthritis; (d) rheumatoid arthritis; with (d) other inflammatory processes and diseases of the autoimmune system, in particular Sjogren's syndrome, chronic tuberculosis of the skin (lupus); ulcerative colitis, Crohn's disease and uveitis; (e) respiratory diseases, in particular asthma; - (g) neurological disorders, in particular multiple sclerosis, Parkinson's disease and Huntington's chorea; Ge) (3) kidney and urinary tract disorders; () cardiovascular diseases; (u) eye tissue diseases, in particular retinal pigmentosis and age-related macular degeneration; (l) mental disorders, in particular schizophrenia, Alzheimer's disease, distracted attention, alcoholism and depression; "(m) hypertrophy of the prostate gland and prostatitis; ssh c (n) impotence and male infertility; and (o) mastalgia; "" (n) male pattern baldness (p) osteoporosis; (c) skin diseases, in particular atopic eczema, hand eczema, psoriasis, urticaria and allergic

Gee! disorders; (t) dyslexia and other hearing disorders; - (in) exhaustion caused by cancer. o 2. 1,3-propanediol as derivatives containing: two fatty acids, where one fatty acid is AA and the other is AA, OSGA, OSA or EPA; are used for treatment under paragraph (1), in particular under points (a), (g), (i), (y), (l), (c) and (t).

Ta» 3. 1,3-propanediol as derivatives containing: two fatty acids, where one fatty acid is EPA and the other is EPA or ONA; are used for treatment under paragraph (1), in particular under points (b), (c), (d), (e), (e), (g), (z), (I), (y), (l ), (p), (t) and (y). 4. 1,3-propane-diol as derivatives, where one position is occupied by a fatty acid from the series SGA, OSI A, AA, ZK, si A, ERA or ONA, and the other position is occupied by an agent selected from the list in the following paragraphs of the text of this ; and F) the chemical structure of this agent can be attached to 1,3-propane-diol with the help of one of the described co-bonds: (a) tryptophan for the treatment of any disease, but mainly for mental, behavioral disorders, because of pain and other ailments, especially depression, sleep disorders and migraines; (b) phenylalanine for the treatment of any disease, especially depression, multiple sclerosis and chronic fatigue syndrome; (c) arginine for the treatment of any disease, especially diseases in which the mechanism of nitric oxide production is distorted; 65 (d) carnitine or carnitine derivatives for the treatment of any disease, especially muscle failure, heart failure, chronic fatigue syndrome, Alzheimer's disease and peripheral neuropathologies; (e) any other amino acid or related substance for the treatment of any disease, or aminolevulinic acid or its derivatives for the treatment of any disease, especially cancer; (e) adenylosuccinate or related substances for the treatment of any disease, especially muscular dystrophy, heart failure, chronic fatigue syndrome and Alzheimer's disease and other forms of dementia; (g) aspirin, salicylic acid, indomethacin, ibuprofen, or any other nonsteroidal anti-inflammatory drug for the treatment of any disease, especially inflammation that causes pain, 7/0 Alzheimer's disease and other forms of dementia, and any disease , in which it is necessary to inhibit the accumulation of small plaques of harmful substances; (3) any antibiotic for the treatment of any relevant infectious disease, especially tetracycline, clindamycin, minocycline, chlortetracycline, and erythromycin for the treatment of acne (inflammation of the sebaceous gland); (Y) any antimalarial or antiprotozoal drug for the treatment of any disease, but in particular drugs such as chloroquine, mepacrine, quinacrine and mefloquine for the treatment of malaria, protozoal disorders, inflammatory processes and schizophrenia; (u) any antifungal drug for the treatment of any disease, especially drugs such as metronidazole and antifungal imidazoles, as well as nitroimidazoles and amphotericin for the treatment of various types of fungal infections; (l) any anti-inflammatory steroid for the treatment of any which disease, especially hydrocortisone and betamethasone for the treatment of skin irritations, and beclomethasone and budesonide for the treatment of asthma; (m) any gonadal steroid for the treatment of any disease, especially estrogens and progestogens for the treatment of uterine insufficiency and osteoporosis , as well as androgens for the treatment of testicular insufficiency; (n) any adrenosteroid for the treatment of any disease, especially dehydroepiandrosterone for i) the treatment of disorders of the body associated with aging processes; (o) any retinoid for the treatment of any disease, particularly tretinoin and isotretinoin for the treatment of skin irritations and for skin care; "g zo (n) any anti-cancer agent for the treatment of cancer; (p) any agent for the treatment of schizophrenia and other forms of psychosis; (c) any antidepressant agent for the treatment of any disease, especially for the treatment of depression itself; or (t) any agent for the treatment of any disorder, primarily anxiety disorder and persecutory mania; -- (y) any immunosuppressive agent for the treatment of any disease, but especially ciclosporin and co-tacrolimus for maintaining control over the state of the immune system after organ transplantation, as well as for the treatment of autoimmune and inflammatory disorders, in particular psoriasis, eczema, asthma , rheumatoid arthritis and inflammatory processes in the intestines, in particular in the gastrointestinal tract; (f) any inhibitor of the injection of active protons or Na2-antagonist for the treatment of any « 0 disease, especially such diseases that are associated with excessive secretion of gastric acid in c or with a reduced protective reaction against excessive gastric acidity; (SO any diuretic drug for the treatment of any disease, primarily for diseases, ;" associated with urinary retention and excessive pressure in the renal-urinary system; (c) any drug - calcium antagonist - for the treatment any disease, especially diseases,

Related to the cardiovascular system;

Ge" (4) any angiotensin-converting enzyme inhibitor or angiotensin antagonist for use in the treatment of any disease, particularly cardiovascular disease; - (w) any beta-passivator (beta-blocker) for the treatment of any diseases, especially cardiovascular diseases; (h) any antiepileptic drug for the treatment of any disease, especially co-phenytoin, carbamazepine, valproate, ethosuximide, vigabatrin or lamotrigine for the treatment of epilepsy; (i) any lipid-lowering agent for the treatment of any disease, especially fibrates and statins capable of lowering and modifying cholesterol; (aa) any oral hypoglycemic agents that increase insulin sensitivity, and 5 Which are used to control the course of diabetes; (66) any bisphosphonates used to control the course of osteoporosis, Paget's disease (F, and cancer); ka (vv) any contrast agents used in radiology, in particular diatrizoate compounds, iodipamide, ioglycamates, iopanoates, iophendylate , iothalamate, ioxaglate, metrizamide and related compounds; 60 (g) any peptide or protein for such treatment of diseases where the peptide or protein itself is used, including insulin, calcitonin, erythropoietin and other peptides; (dd) any vitamin, used in the treatment of any disease, or added to foods, nutrients or nutritional supplements, through the use of which that vitamin is better absorbed; (ee) any antioxidant used to control the course of any disease, 65 especially such , in which antioxidants are vital compounds, including cardiovascular, cancer, and inflammatory processes; any antioxidant used as a food product, or i k product component, nutrient or food additive; (jj) any porphyrin chlorin or bacteriochlorin-based drug, especially their tetrakis(hydroxyphenyl)-derivatives used in photodynamic cancer therapy.

Ease of synthesis compared to triglycerides

Synthesis of triglycerides

The next section illustrates the advantages of using 1,3-propanediol, particularly compared to triglycerides.

It is proposed to use 1,3-propane-diol instead of glycerol in the esterification of fatty acids, especially in the case when only one type of fatty 7/0 acid (for example, linolenic acid) is attached to the carbon-triatom chain "backbone" of the molecule. Although diesters and triglycerides are very similar chemically, the production of diesters can be carried out under very strict technological requirements, and the final result can be obtained in a matter of hours. The production of triglycerides requires more complex technological conditions, as well as the use of fatty acid chlorides or biocatalysts (the production reaction in this case takes several weeks). Briefly, the method of synthesizing triglyceride can be characterized as follows: a chemical reaction with /5 metals, metal chlorides or organic acids as catalysts; use of fatty acid chlorides; use of fixed enzymes (enzymes).

All processes using acids, metals or metal chlorides as catalysts are very similar and have a standard list of advantages and disadvantages. Many problems are caused by the specificity of the technique, for example, acidic conditions and high temperatures (from 1407°C to 180°C) during the course of reactions. Application of the 2nd method of r-TZA. perhaps minimizes the problems, since it provides the most considered for known technologies of this type of conditions (1407C). The reaction of glycerol with chlorides of fatty acids is carried out in a "cold" state, but during its course toxic gases are released, and besides, without careful supervision, you can lose control over such a reaction. This technique assumes that the fatty acid chlorides themselves must first be produced - an additional procedure that negatively affects the efficiency of the entire process. For the catalysis of these reactions under very mild conditions (about 60"C), a specific series of enzymes called lipases can be used, and when polyunsaturated fatty acids are used, a choice of catalysts is possible. But it should be noted, i) that most enzymes are the most effective interact with the 1- and 3-positions of glycerol in a different way. The addition of a fatty acid to the 2-position is slow and often depends on "acyl migration", i.e. the fatty acid must first be attached to the 1- or 3-position, after which it migrates to 2-position, where "g" remains chemically attached to the molecule. Thus, as noted earlier, the reaction of triglyceride synthesis, catalyzed by enzymes (enzymes), can last for many days until its final completion. Theoretically, for esterification 1, to 3-propanediol, the same technique as for glycerol can be applied, however, if attention is paid to the fact that the enzymes catalyze preferentially the addition of fatty acids to the 1- and 3-positions of glycerol, it becomes apparent m exceptional efficiency of these enzymes in the production of complex diesters. | indeed, the reaction can be completely completed in a matter of hours at even lower temperatures (from 45°C to 60°C) than those required for triglyceride synthesis. After four hours the fatty acid disappears from the reaction, and after eight hours the output of the diester can exceed 9595, the rest of the volume is occupied by the monoether.

Additional complications in triglyceride synthesis are due to the presence in the glycerol molecule of both primary and secondary hydroxyl groups, as well as a prochiral center (central carbon atom). Such problems can be solved by using carefully selected protecting groups and synthesizing chiral centers. But this leads to excessive multi-stage synthesis, which significantly reduces the effective. output and increases the level of excess impurities due to their summation at each stage. On the contrary, huh?" 1,3-propanediol contains only one primary hydroxyl group and has no prochiral centers at all.

Accordingly, the synthesizing process is reduced to two stages (maximum), while the efficiency of the useful output increases and the level of unwanted impurities decreases.

Summing up, it should be noted that the reaction of obtaining complex diesters from polyunsaturated fatty acids and 1,3-propane proceeds faster and under milder conditions than those necessary for the corresponding reaction of triglyceride synthesis. o Pharmaceutical prescription

The pharmaceutical prescription of the compounds can be drawn up in any convenient form that is acceptable to specialists in the manufacture of medicines, skin care preparations and food additives, they can be administered orally, through the small intestinal tract, superficially, parenterally ( subcutaneously, intramuscularly and intravenously), through the rectum, vaginally or by any other acceptable method.

Like triglycerides, 3-propanediol diesters, especially those containing two fatty acids, can be easily emulsified with phospholipid or, even better, galactolipid

F) emulsifiers. Such emulsions are mainly convenient for introduction into the body by oral, small intestinal and intravenous routes.

For example, complex diesters of fatty acids (FFAs) are found in practice in the form of a free pourable or oily substance, therefore, they can be prescribed pharmaceuticals in the following way: 1. Production of the 20905th diester emulsion of SGA and ERA with 1,3-propane-diode Emulsions for for oral administration are made using homogenization under high pressure. The particle size distribution and zeta potential of the resulting emulsions were determined using the dynamic light scattering method at room temperature. Plaque measurements were performed at room temperature (7eyavigeg 4 Maimegp 65 Ipvigitepiv I itied). An oil-water emulsion (portion of 200 g) containing the following components was produced:

The galactolipid emulsifier was dispersed in dieether and mixed with vitamin E, AP and water. 70 The oil phase was added to the phase of the aqueous solution using a powerful mechanical mixer (Shygaishgtah) at speed 4 for several minutes. After that, this semi-emulsion was homogenized under a pressure of 80 Mpa at a temperature of 507C for 6 cycles (mini-laboratory 8.30 N; ARM Kappie AB, Denmark). The average size of elementary droplets in the obtained emulsion was about 23 Ohm. Potassium sorbate and sweeteners were also added to this oral emulsion. 75 2. Production of the 20905th emulsion of SGA and ERA diester with 1,3-propane-diol for intravenous administration into the body

200 g of oil-water emulsion containing the following components was prepared in a similar way:

Components to

Emulsifier 2.00

Dyefir (SGA-ERA) 20.00

Glycerin 2.0

Water 100.00

This emulsion, which was homogenized under high pressure for 6 minutes, consisted of elementary c droplets with an average size of 211 nm and a zeta potential of 40 mV. The obtained emulsion was either filtered (3) through a membrane with a pore size of 0.22 microns or treated in an autoclave to change the droplet size.

The doses of active substances that can be introduced into the body vary widely from 1 mg to 200 g per day, optimally they can be from 10 mg to 10 g (the most optimal - from 10 mg to 3 g), in accordance with their type . In the treatment of cancer, optimal doses can range from 2 to 150 g per day. According to the situation, these emulsions can be used topically in preparations where active substances (ee) for local use are contained from 0.00195 to 5095, optimally from 0.0595 to 2095, and most optimally from 0.196 to 10965.

Examples of h-

The synthesis of non-steroidal anti-inflammatory drugs (NSAIDs) chemically attached to fatty acids was covered in the published EPA-00 675 103, which the authors of the present invention have already referred to earlier. uh-oh

An overview of the synthesis of the chemical bond of fatty acids via a 1,3-propane-diol radical residue is offered below in the text, along with other general illustrative material.

Example 1 « 1,3-(di-2,2,2-octadeca-6,9,12-trienoyloxy)propane 7 70 (OHA diester with 1,3-propanediol) c Solution of 1,3-dicyclohexylcarbodiimide (1 .07 g) and 4-"M,M-dimethylamino) pyridine (0.59 g) in methylene chloride with (5 ml) was added to a solution of 1,3-dihydroxypropane (0.152 ml) and 7,2,2-octadeca-6 of ,9,12-trienoic acid (9595, 1.36 g) in methylene chloride (15 ml). The reaction mixture was stirred at room temperature under an artificially created nitrogen atmosphere until complete dissolution, which was determined by adding 39 TLC (thin layer chromatography)|-hexane (80 mL) to the reaction. The precipitate was removed by filtration and thoroughly

F washed with hexane. The combined filtrates were concentrated and purified using single (flash) chromatography, after which 1,3-(di-2,7,2-octadeca-6,9,12-trienoyloxy)propane was obtained as a pale yellow free pourable oily substance.

Me Example 2 (ee) 20 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(2-octadeca-9-enoyloxy)propane,

T" (Diester of OA and oleic acid with 1,3-propane-diol)

Part 1:

A solution of 2,2,2-octadeca-6,9,12-trienoic acid (150 g) in methylene chloride (500 ml) was added dropwise to a mixture of 1,3-dihydroxypropane (205 g) 1,3-dicyclohexylcarbodiimide (130 g ) and 59 4-(M,M-dimethylamino)pyridine (87 g) in methylene chloride (2500 ml) at room temperature under nitrogen

HF) atmosphere. When TLC showed complete reaction, the reaction mixture was filtered. The filtrate was washed with dilute hydrochloric acid, water-saturated sodium chloride solution.

The solution was dried, concentrated and purified by dry column chromatography to give 1-(7,72,2g-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane as a pale yellow oily substance. because Part 2:

A solution of 1,3-dicyclohexylcarbodiimide (23.7 g) and 4-(M,M-dimethylamino)pyridine (15.9 g) in methylene chloride (200 mL) was added to a solution of 1-(7,2,2-octadeca-6 ,9,12-trienoyloxy)-3-hydroxypropane (33.6 g) and 2-octadeca-9-enoic acid (30 g) in methylene chloride (400 ml) under a nitrogen atmosphere at room temperature.

After the completion of the reaction, which was confirmed by HTS analysis, the obtained solution was diluted in hexane, filtered, concentrated and purified using dry chromatography, the output was obtained

1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(2-octadeca-ZU-enoyloxy)propane in the form of a pale yellow free-flowing oily substance.

Example C 1,3-(di-2,2,2-octadeca-6,9,12-trienoyloxy)-3-(7,7,7,72,2-eicose-5,8,11,14,17 -pentaenoxy)propane. (Diester OGA and ER A with 1,3-propane-diol)

The preparation is similar to example 2, part 2, but with the replacement of 2-octadeca-9-enoic acid with 7,7,7,7,7-eicose-5,8,11,14,17-pentaenoic acid. At the output, chromatography showed 1,3-(di-2,2,2-octadeca-6,9,12-trienoyloxy)-3-(7,7,7,72,2-eicose-5,8,11,14 ,17-pentaenoxy)propane in the form of 70 pale yellow oily substance.

Example 4 1,3-di(2,72,2-octadeca-6,9,12-trienoyloxy)propane (Diether CA with 1,3-propane-diol)

Prepared as in Example 2, Part 2, but replacing 2-octadeca-U-enoic acid with 7,7,7-octadeca-6b,9,12-triegenoic acid. At the output, chromatography showed 1,3-di(2,72,2-octadeca-6,9,12-trienoyloxy)propane as a pale yellow substance.

Example 5 (5)-1-(1,2-dithiolane-3-pentanoyloxy)-3-(7,72,2-octadeca-6,9,12-trienoyloxy)propane. (Diester of lipoic acid and 01 A with 1,3-propane-diol)

A mixture of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) and 4-(N,M-dimethylamino)pyridine (480 mg, 3.98 20 mmol) in tert-butyl methyl ether (15 mL) was added to a mixture of lipoic acid (645 mg, 3.12 mmol) and 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-33-hydroxypropane (1 g, 3 mmol) in tert-butyl methyl ether ( 30 ml).

The mixture was kept at room temperature under a nitrogen atmosphere for 5 hours, the development of the reaction was monitored with the help of HTS (4095 ethyl acetate/hexane). At the end of the reaction, the mixture was filtered, concentrated and purified using one-time (flash) chromatography (hexane, 295 ethyl acetate/hexane, s re ethyl acetate/hexane and at the end 1090 ethyl acetate/hexane), yielding (5)-1-(1, 2-dithiolane-3-pentanoyloxy)-3-(7,72,2-octadeca-6,9,12-trienoyloxy)propane in the form of a viscous yellow i) oily substance.

Example 6 1-F21-5-fluoro-2-methyl-1-(4-methylsulfinyl)benzylideneindene-3-acetyloxy)-3-(2,7,2-octadeca-6,9,12-trienoic) loxy)propane (Diester of sulindac acid and OGA with 1,3-propanediol) A solution of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) in tert-butyl methyl ether (30 mL) was added to a mixture of sulindac (1, 12 g, 3.15 so

MMmOlo), 4-(M,M-dimethylamino)tridine (480 mg, 3.9 MMmol) and o 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g , C mmol) in tert-butyl methyl ether (15 ml).

The mixture was stirred and kept at room temperature under nitrogen for 5 hours, the development of the reaction (7

Controlled by HTSH (4095 ethyl acetate/hexane). After completion, the mixture was filtered, He was concentrated and purified by means of one-time (flash) chromatography (4095 ethyl acetate/hexane, then 500% ethyl acetate/hexane and at the end of the fight ethyl acetate/hexane), the output was 1-FI1-5-fluoro-2-methyl -1-I4--methylsulfinyl)benzylideneindene-3-acetyloxy)-3-(2,2,2-octadeca-6,9,12-trienoyloxy)propane in the form of a waxy (wax-like) yellow solid. with c Example 7 1-(K)-3-acetoxy-4-(trimethylammonio|butyroyloxy)-3-(7,2,2-octadeca-6,9,12-trienoyloxy)propane. ;" (Diester of acetyl carnitine and OA with 1,3-propane-diol)

Freshly distilled thionyl chloride (1.5 mL) was slowly added to (K)-acetylcarnitine (ligroir) in a pear-shaped flask. During the reaction, it was carefully monitored that the reagents were localized at the bottom of the flask, to

Ge" at the moment of obtaining a transparent solution. 4 hours after the start of the reaction at room temperature, the excess thionyl chloride was removed under reduced pressure (keeping the temperature of the solution in the flask no higher than 30°C). Thus, chloride anhydride was obtained at the output in the form of a highly hygroscopic white solid, which is immediately was used without further purification.1-(di-2,7,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1.4 g, 4.17 mmol) was added to the flask and dry tetrahydrofuran (THF) (4 mL). The mixture was allowed to stand overnight at room temperature. Chromatographic analysis (4095 ethyl acetate/hexane) showed complete reaction. The reaction mixture was added dropwise to hexane (250 mL) with vigorous stirring. . A fine-grained precipitate was formed, which was collected by centrifugation. After removing the layer that appeared on top after settling, the obtained solid fraction was again transformed into a suspension in hexane and centrifuged. After that, the the procedure of washing with hexane and finally obtained at the exit

F) 1-(K)-3-acetoxy-4-(trimethylammonio|butyroyloxy)-3-(7,2,2-octadeca-6,9,12-trienoyloxy)propane. ka Example 8 1-(3,3-dimethyl-7-oxo-6-(|phenoxyacetyl)amino)-4-thia-1-azabicyclo|3.2.0)heptan-2-oyloxy)-3-(7,2 ,2-OoCTadec in α-6,9,12-trienoyloxy)propane. (Diester of penicillin M and OA with 1,3-propanediol)

A mixture of penicillin M (1 g, 2.9 mmol), 1-(72,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (860 mg, 2.6 mmol), 1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4-(M,M-dimethylamino)pyridine (in the catalyst volume) in dichloromethane (30 mL) was stirred and left overnight at room temperature. The reaction mixture was then diluted with hexane (50 mL), filtered and concentrated to dryness. The residue was washed with hexane (3 x 50 mL) to remove the remaining unreacted 1-(7,7,2-octadeca-6,9,12-trienoyloxy)-33-hydroxypropane. The semi-solid residue was dissolved in diethyl ether (150 mL), washed with water (100 mL) and dried. The ethereal solution was diluted in hexane (125 mL), after which the solution was filtered through a silica pad (4 cm × 4 cm). The filtrate was concentrated to yield 1-(3,3-dimethyl-7-oxo-6-( |phenoxyacetyl)amino)-4-thia-1-azabicyclo|3.2.0)heptan-2-oyloxy)-3-(7,2,2-octadeca-6, 9,12-trienoyloxy)propane in the form of a viscous colorless liquid.

Example 9 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetyloxy)propane. (of diephyrindomethacin and SGA with 1,3-propanediol) 70 A solution of 1,3-dicyclohexylcarbodiimide (58 g, 0.28 mol) and 4-(«M,M-dimethylamino)pyridine (37.9 g, 0.31 mol) in methylene chloride (800 mL) was added with stirring to a solution of 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (79.5 g, 0.24 mol) and indomethacin (93.2 g, 0.26 mol) in methylene chloride (400 ml) at room temperature under an artificial nitrogen atmosphere.

Stirring continued for 3 hours. The mixture was filtered, concentrated and purified by dry 7/5 column chromatography (ethyl acetate/hexane). Fractions of the obtained product were collected after settling and concentrated, the final yield was 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(1-(4-chlorobenzoyl)-5-methoxy-2 -methyl-indole-3-acetyloxy)propane in the form of a bright yellow viscous oily substance.

Example 10 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(2-pyrrolidine carboxy)propane (Diester of proline and OGA with 1,3-propanediol)

Part 1: 1,3-Dicyclohexylcarbodiimide (674 mg, 3.3 mmol) and 4,4-(N,M-dimethylamino)pyridine (472 mg, 3.9 mmol) in methylene chloride (20 mL) were added at stirring to a SOLUTION of 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and MAVOS-proline (671 mg, 3.12 mmol) in methylene chloride (20 ml) at room temperature under nitrogen. Stirring lasted for 7 hours, after which i) the mixture was left overnight at room temperature. The mixture was filtered and purified by column chromatography (methanol/methylene chloride), yielding 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(M-BOSC-pyrrolidine carboxy)propane in in the form of a yellow oily substance. Part 2:

The chemically protected product of the first part of the reaction was dissolved in 1095 anisole/trifluoroacetic acid so (10 mL) and left at room temperature under nitrogen for 30 minutes. After the HST analysis, which showed that the deprotection was complete, the mixture was purified by column chromatography (890 methanol/42 uomethylene chloride/5090 ethyl acetate), yielding 77 1-(2,2,2-octadeca-6,9 ,12-trienoyloxy)-3-(2-pyrrolidine carboxy)propane in the form of a viscous substance with a yellow-brown color.

Example 11 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(2-amino-3-indolylropanoyloxy)propane. (Diester of tryptophan and OGA with 1,3-propane-diol) "

Part 1: from c A solution of 1,3-dicyclohexylcarbodiimide (674 mg, 3.3 mmol) and 4-(N,M-dimethylamino)pyridine (472 mg, 3.9 mmol) in methylene chloride (20 mL) was added at stirring to the solution and? 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and M-BOC-tryptophan in methylene chloride (20 mL) at room temperature under nitrogen. Stirring lasted for 7 hours, after which the mixture was

Left overnight at a temperature of 0"C. The mixture was filtered and purified using a column

Ge» chromatography (methanol/methylene chloride), 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(M-80С-2-amino-3-indolylropanoyloxy) propane was obtained as yellow - oily substance.

Go! Part 2:

The chemically protected product was dissolved in 1095 anisole/trifluoroacetic acid (6.1 mL) and left at room temperature under nitrogen for 15 minutes. After chromatographic analysis, which revealed complete deprotection, the mixture was purified by column chromatography (895 methanol/4290% methylene chloride/5090% ethyl acetate) to yield 1-(2,2,2-octadeca-6,9, 12-trienoyloxy)-3-(2-amino-3-indolylropanoyloxy) propane in the form of a viscous or paraffinic red substance.

Example 12

F) 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(o-amino-D-phenyl-propynyloxy)propane. ko (Diester of phenylalanine and OA with 1,3-propanediol)

Part 1: in a solution of 1,3-dicyclohexylcarbodiimide (1.77 g, 8.57 mmol) and 4-(«M,M-dimethylamino)pyridine (1.24 g, 10.13

MMmol) in methylene chloride (30 mL) was added with stirring to a solution of 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (2.62 g, 7.79 mmol) and M -BOC-phenylalanine (2.17 g, 8.18 mmol) in methylene chloride (30 mL) at room temperature under nitrogen. Stirring lasted for 7 h, after which the mixture was left overnight at a temperature of 07 C. Then the mixture was filtered and purified using column chromatography, yielding 1-(2,2,2-octadeca-6,9,12-trienoyloxy) )-3-(M-BOsC-x-amino-d-phenyl-propionyloxy) propane in the form of a yellow oily substance.

Part 2:

The chemically protected product was dissolved in 1095 anisole/trifluoroacetic acid (17 mL) and left at room temperature under nitrogen for 30 minutes. After chromatographic analysis, which revealed complete deprotection, the mixture was also purified by column chromatography (895 methanol/429omethylene chloride/5090o ethyl acetate) to yield 1-(2,2,2-octadeca-6,9,12- trienoyloxy)-3-( d-amino-VD-phenyl-propynyloxy)propane in the form of a yellow viscous oily substance.

Example 13 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(4-aminobutanoyloxy)propane. (Diester of aminobutyric acid (SABA) and OSI A with 1,3-propane-diol)

Part 1:

A solution of 1,3-dicyclohexylcarbodiimide (0.84 g, 4.06 mmol) and 4-(N,M-dimethylamino)pyridine (0.59 g, 4.79 75 mmol) in methylene chloride (ml each) was added with stirring to a solution of 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1.24 g, 3.69 mmol) and M-AVOS-ZAVA (0.75 g, 3, 69 mmol) in methylene chloride (15 mL) at room temperature under nitrogen. Stirring lasted for 7 h, after which the mixture was left overnight at a temperature of 0"C. Then the mixture was filtered and purified using column chromatography (ethyl acetate/hexane), yielding 1-(2,72,2-octadeca-6 ,9,12-trienoyloxy)-3-M-BOC-4-aminobutanoyloxy)propane in the form of a colorless oily substance.

Part 2:

The chemically protected product was dissolved in 1095 anisole/trifluoroacetic acid (10.5 mL) and left at room temperature under nitrogen for 30 minutes. After chromatographic analysis, which revealed complete deprotection of Hα, the mixture was purified by column chromatography (895 methanol, 4290 methylene chloride/5095 ethyl acetate) to yield 1-(7,72,2-octadeca-6,9 ,12-trienoyloxy)-3-(4-amino o butanoyloxy)propane in the form of a yellow oily substance.

Example 14

3,3-thio-di-(1-propionyloxy-(3-(2,2,2-octadeca-6,9,12-trienyloxy)-propane)). "I (Double ester of CA and 1,3-propane-diol with 3,3'-thiodipropionic acid).

A solution of 1,3-dicyclohexylcarbodiimide (660 mg, 3.22 mmol) and 4-(M,M-dimethylamino)pyridine (445 mg, 3.64 so

MMmol) in methylene chloride (per mL) was added with stirring to a solution of 1-(2,2,2-octadeca-6,9,12-trienyloxy)-3-hydroxypropane (940 mg, 2.8 mmol) and C, of 3-thiodipropionic acid (250 mg, 1.4 mmol) in methylene chloride (3 mL) at room temperature under nitrogen. Stirring lasted 4 hours. -

The mixture was diluted with hexane (50 mL), filtered, concentrated, and purified by flash chromatography (ethyl acetate/hexane). The product fractions were then separated and concentrated to yield 3,3-thio-di-(1-propionyl -(3-(72,7,2-octadeca-6,9,12-trienyloxy)-propane)) in the form of a colorless oily substance.

Example 15 1-(1-(2,2,2-octadeca-6,9,12-trienoyloxy)-33-propyl)-4-(7,72,2-octadeca-6,9,12-trienyl)butane- 1,4-dioate. - c (Diester (SGA monoester with 1,3-propanediol) and OGA alcohol with succinic acid). Part 1: "» A mixture of 1-(72,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (10 g, ZOmole) and succinic anhydride (3 g, ZOmole) in dry tetrahydrofuran ( TNE) (100 ml) was stirred at room temperature until the solution became clear.

Ge") This solution was cooled to 0"C, after which a solution of -3z 1,8-diazabicycloi|5,4.0)undec-7-ene (4.5 ml, 30 mmol) in dry TNE ( 50 ml).

Three hours later, chromatographic analysis showed that most of the monoester had already reacted. A few more crystals of succinic anhydride were added to the (oo) mixture, after which the following 30 waves. the solution was stirred. The reaction mixture was diluted with diethyl ether (250 mL) and washed with 2M hydrochloric acid (2 x 250 mL), water (250 mL), and brine (250 mL). The product was then dried (sodium sulfate) and concentrated to dryness. Then the material was used without any additional purification.

Part 2:

Oxalyl chloride (3.9 mL, 45 mmol) was added to a solution of the product of the first part of the reaction (13 g, 30 mmol) in methylene chloride (75 mL). The mixture was stirred at room temperature under nitrogen for 2 h, after which it was concentrated to dryness. Next, hexane (75 mL) was added and the product was again concentrated to dryness. This procedure was repeated twice, with the addition of 75 ml of hexane each time. Then the material was used without any additional purification. 60 Part 3:

A solution of hydrogen chloride obtained in the second part of the reaction (1 g, 2.2 mmol) in methylene chloride (10 ml) was added dropwise to a solution of 2,2,2-octadeca-6,9,12-trienol (635 mg, 2.4 mmol ), triethylamine (1 ml, 7.2 mmol) and 4-(M,M-dimethylamino)pyridine (in the volume of the catalyst) in methylene chloride (20 ml) at room temperature. At the end of the reaction, the mixture was concentrated and purified using single chromatography (ethyl acetate/hexane); 1-(1-(2,2,2-octadeca-6,9,12-trienoyloxy)-33-propyl)-4-(7,72,2-octadeca-6,9,12-trienyl) butane-1,4-disat.- in the form of a colorless oily substance.

Example 16 1-(2,3,5-triiodobenzoyloxy)-3-(7,72,2-octadeca-6,9,12-trienoyloxy)propane. (Diester of 2,3,5-triiodobenzoic acid and CA with 1,3-propanediol) 2,3,5-Triiodobenzoyl chloride (1.54 g, 3.08 mmol) was added to a mixture of 1-(7,2,2 -octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and triethylamine (1 mL) in methylene chloride (80 mL), after which the resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was then concentrated and purified by flash chromatography (ethyl acetate/hexane); 70 1-(2,3,5-triiodobenzoyloxy)-3-(7,72,2-octadeca-6,9,12-trienoyloxy)propane were obtained as a result.

Example 17 (5)-1-(1,2-dithiolane-3-pentanoyloxy)-3-(7,7,7,7,7,72-dOKOZA-4,7,10,13,16,19-hexaenoyloxy) )propane. (Diester OGA of talipoidic acid with 1,3-propane-diol)

Part 1:

A solution of 2,2,2,2,72,2-doCkOoZa-4,7,10,13,16,19-hexaenoic acid (6.4 g, 19.5 mmol) in methylene chloride (225 mL) was added dropwise to a solution of 1,3-propanediol (7.5 g, 99 mmol), 1,3-dicyclohexylcarbodiimide (4.65 g, 20 mmol) and 4-(M,M-dimethylamino)pyridine (2.1 g, 17 mmol) in methylene chloride (225 ml) at a temperature of -1070. The reaction mixture was stirred overnight, gradually increasing the temperature to room temperature. The reaction product was filtered, concentrated and purified by flash chromatography (ethyl acetate/hexane); 1-(72,72,72,72,7,7-DdoKkOZa-4,7,10,13,16,19-hexaenoyloxy)-3-hydroxypropane was obtained as a pale yellow oily substance.

Part 2:

To a mixture of 1-(2, 2,2,2,2,7docosa-4, 7, 10, 13, 16, 19-hexaenoyloxy)-3-hydroxypropane (1.16 g, 3 mmol) with lipoic acid (645 mg, 3.12 mmol) and methylene chloride (15 ml). In 2.5 hours after that, the mixture was filtered at room temperature under i) nitrogen, concentrated and purified by flash chromatography (ethyl acetate/hexane); obtained / (5)-1-(1,2-dithiolane-3-pentanoyloxy)-3-(2,2,72,2,7,7-DdOKOZA-4,7,10,13,16,19 -hexaenoyloxy) propane in the form of a yellow oily substance. Example 18

Methyl di(2,2,2-octadeca-6,9,12-trienoyloxypropyl)-phosphate. co (Phosphotriester of 2 molecules of the complex 3-hydroxypropyl ether OSGA and 1 molecule of methanol) co

Part 1:

Triethylamine (3.74 mL, 26.8 mmol) was added dropwise to a cooled (07C) solution of freshly distilled phosphorus oxychloride (2.74 g, 17.9 mmol) in anhydrous tetrahydrofuran (15 mL). a solution of 1-(7,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane in anhydrous) tetrahydrofuran (15 ml) was added dropwise to the mixture. The reaction temperature did not exceed 10"C, and the reaction itself took place under an artificial nitrogen atmosphere. Chromatographic analysis performed 15 minutes later showed complete disappearance of the starting material. The mixture was filtered and concentrated. Then, toluene (50 ml) was added, and the mixture was concentrated again. The procedure with toluene (also 50 ml each) was repeated twice. with Part 2: ;" A solution of // 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (3 g, 9 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise to a solution of crude phosphochloridate (7, 5 mmol) (half of the portion prepared in the first part of the reaction) and triethylamine (3.2 mL, 22.5 mmol) in anhydrous

He» tetrahydrofuran (20 ml) at room temperature under nitrogen. The reaction lasted for 24 hours at a temperature not exceeding 107C. Methanol (15 mL) was then added and the reaction was continued at room temperature until chromatographic analysis showed that said phosphochloridate was completely reacted

Go! and formed the necessary complex phosphotriester. Methyl di(27,2,2-octadeca-6,9,12-trienoyloxypropyl)-phosphate was obtained by separation on a chromatographic column (ethyl acetate/hexane) in the form of a colorless oily substance. Example 19

Di(27,2,2-octadeca-6,9,12-trienoyloxypropyl)-phosphate. (Phosphodiester of 2 molecules of 3-hydroxypropyl ether SG A)

Lithium bromide (104 mg, 1.13 mmol) in methyl ethyl ketone (1 mL) was added to a solution of methyl di(2,2,2-octadeca-6,9,12-trienoyloxypropyl)-phosphate (0.85 g , 1.13 mmol) (production, similar

F) of example 18) in methyl ethyl ketone (1 ml), after which the mixture was heated with reverse cooling for 1 hour. After final cooling, the mixture was dissolved in diethyl ether (3 mL) and extracted into water (3 mL). The resulting emulsions were separated by adding a few drops of methanol. The organic layer was separated, dried (sodium sulfate), concentrated and isolated by chromatography (methanol/chloroform); di(7,2,2-octadeca-6,9,12-trienoyloxypropyl)-phosphate was obtained as a white solid paraffin-like substance.

Example 20 (2-aminoethyl)-(7,2,2-octadeca-6,9,12-trienoyloxypropyl)phosphate. 65 (Phosphodiester of ethanolamine and 3-hydroxypropyl ether of OSI A)

Part 1:

A mixture of ethanolamine (0.5 mL, 8.25 mmol) and triethylamine (4.2 mL, 30 mmol) in anhydrous tetrahydrofuran (20 mL) was added to a solution of crude phosphochloridate (7.5 mmol) (half of the portion that was prepared in example 18, part 1) also in anhydrous tetrahydrofuran (20 ml), keeping the reaction temperature no more than 107C. The progress of the reaction was monitored by chromatography. The mixture was left for 3 days at a temperature not exceeding 5"C. After that, it was filtered, concentrated, diluted with hexane (50 ml) and concentrated a second time.

Part 2:

The product obtained after the first part of the reaction was dissolved in isopropanol (100 ml), acetic acid (70 ml) and water, after which the solution was allowed to settle under a nitrogen atmosphere at room temperature. When chromatography confirmed complete reaction, the mixture was concentrated and partitioned between acetonitrile (50 mL) and hexane (50 mL). The hexane layer was separated, concentrated and purified by flash chromatography (methanol/chloroform/water). The purified fractions were separated and concentrated. Addition of ethyl acetate resulted in a precipitate of (2-aminoethyl)-(7,2,2-octadeca-6b,9,12-trienoyloxypropyl)phosphate as a cream-colored paraffinic solid, which was collected by centrifugation.

Example 21 (2,72,2-octadeca-6,9,12-trienoyloxypropyl)-(2-(M,M,M-trimethylammonium)ethyl)phosphate. (Phosphodiether of the knee and Z-hydroxypropyl ether SI A)

Part 1:

A solution of 2-chloro-1,3,2-dioxaphospholane-2-oxide (430 mg, 3.4 mmol) in toluene (5 mL) was added to a cooled (07) solution of 1-(7,2,2-octadeca- 6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.98 mmol) and triethylamine (0.57 mL, 4.1 mmol) in toluene (4.5 mL). The mixture was left and stirred until the morning, gradually it warmed up to room temperature. After that, chromatography showed that the reaction did not take place completely. Additional portions of triethylamine (0.3 mL) and 2-chloro-1,3,2-dioxaphospholane (200 mg) (as a solution in toluene (5 mL)) were then used, after which the reaction was continued overnight. After that, i) chromatography showed that the reaction was complete, and the mixture was concentrated.

Part 2:

The crude product of the first part of the reaction was dissolved in acetonitrile (60 mL). A quarter of the volume of this solution (g 15 ml) and trimethylamine (10 ml) were heated in a sealed tube at 60°C under a pressure of 5 atm (CAUTION)!). The reaction mixture was cooled and concentrated under a stream of nitrogen; (2,72,2-octadeca-6,9,12-trienoyloxypropyl)-(2-(M,M,M-trimethylammonium)ethyl)phosphate.

Example 22 (2,72,2-octadeca-6,9,12-trienoyloxypropyl)phosphate. -- (Phosphomonoester Z-hydroxypropip-efgr SI A). "at

A solution of 1-(72,727,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1.95 g, 5.5 mmol), pyridine (1.41 mL, 17.3 mmol) and anhydrous tetrahydrofuran ( 15 ml) was added dropwise with stirring to a cooled (07C) solution of phosphorus oxychloride (1.02 g, 6.6 mmol) in anhydrous tetrahydrofuran (5 ml), and the resulting mixture was left for 3 h. at a temperature of 0"C. An aqueous solution of sodium bicarbonate (10905 vol., 10 ml) was added to the reaction mixture. After 20 minutes of stirring, the mixture was poured into ice water (30 ml), after which the pH of the solution was adjusted to 1 by the dropwise addition of 2M hydrochloric (hydrochloric) acid. The mixture was then extracted with diethyl ether (2 x 30 mL). The ether extracts were combined, dried, and concentrated. The resulting oily substance was azeotroped with dry pyridine; (7,2,2-octadeca-6,9,12-trienoyloxypropyl)phosphate was obtained as a viscous, oily yellow substance.

Example 23

He» Methyl-(2,2,2-octadeca-6,9,12-trienoyloxypropyl)-(d-tocopheryl) phosphate. (Phosphotriester of A-tocopherol, methanol and C-hydroxypropyl ether SI A). - Part 1: o Triethylamine (7.5 mL) was added to a solution of freshly distilled phosphorus oxychloride (1.26 g, 8.25 mmol) in anhydrous tetrahydrofuran (7.5 mL) at room temperature. After 15 minutes, a solution of 1-(7,7,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (2.5 g, 7.5 mmol) in anhydrous

Ta» tetrahydrofuran, and that process lasted 30 minutes also at a temperature of 0"C. After the addition, the solution was stirred for the next 30 minutes at the same temperature. Then, dropwise at 107"C, it was added

A-tocopherol (3.23 g, 7.5 mmol) in anhydrous tetrahydrofuran, and the resulting mixture was then stirred also at 107C for 1 hour and left overnight, gradually warming to room temperature.

Part 2: iF) A quarter of the volume of the mixture that was prepared in the first part of the reaction, triethylamine (0.8 mL, b mmol) and methanol (10 mL) were stirred overnight under nitrogen at room temperature. The reaction mixture was concentrated and partitioned between ethyl acetate (30 mL) and water (20 mL), with sodium chloride and methanol added to de-emulsify. The ethyl acetate layer was dried, concentrated and purified by flash chromatography (chloroform); Methyl-(2,72,2-octadeca-6,9,12-trienoyloxypropyl)-(o-tocopheryl)phosphate was obtained as a result.

Example 24 (2,2,2-octadeca-6,9,12-trienoyloxypropyl)-(d-tocopheryl)phosphate. 6E (Phosphodiester of A-tocopherol and Z-hydroxypropyl-ephgru OSI A).

Triethylamine (2 mL) and water were added to a fourth portion of the reaction mixture prepared according to the example

23, Part 1. The mixture was kept under nitrogen in an ice bath for 1 hour, acidified to pH 1 with 2M hydrochloric acid, and extracted with ethyl acetate (20 mL) and methanol (5 mL). The extract was dried, concentrated and purified by flash chromatography (chloroform); 8 0 (Dach-octadeca-6,9,12-trienoyloxypropyl)-(o-tocopheryl)phosphate was obtained as a result.

Example 25 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-5-(2,72,7,72,2-eicose-5,8,11,14,17-pentaenoyloxy)pentane . (Diester OGA and ER A with 1,5-pentane-diol)

Part 1: 70 7,7,7:Octadeca-6,9,12-trienoyl chloride (2 g) was added dropwise to a solution of 1,5-dihydroxypentane (3.5 g), triethylamine (0.94 mL) and 4 -(M,M-dimethylamino)pyridine (0.2 g) in methylene chloride (50 mL) with stirring at 0"C under nitrogen. Upon completion of the reaction, which was determined by chromatography, the reaction mixture was washed with dilute hydrochloric acid and water, dried and column chromatography isolated 1-(2,727,2-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane as a pale yellow 7/5 oil.

Part 2:

The sequence of procedures was similar to example 2, part 2, but instead of 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane, 1-(2,2,2-octadeca-6,9 ,12-trienoyloxy)-5-hydroxypentane, and instead of 7-octadeca-9-enoic acid, 7,7,7,7,7-eicose-5,8,11,14,17-pentaenoic acid was introduced into the reaction. At the exit of Kk! columns obtained 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-5-(2,7,7,72,2-eicose-5,8,11,14,17-pentanoyloxy)pentane . 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-5-(72,7,7,7,2-eicose-5,8,11,14,17-pentaenoyloxy)pentane.

Example 26 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-4-(72,7,7,72,72-eicose-5,8,11,14,17-pentaenoyloxy)benzene . c (Diester SGA and ERA from 1,4-dihydroxybenzene).

The production process is similar to example 25, parts 1 and 2, but in the first part of this reaction, 1,4-dihydroxybenzene was introduced instead of 1,5-dihydroxypentane, and tetrahydrofuran was used instead of methylene chloride as a solvent. 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-4-(72,7,7,72,72-eicose-5,8,11,14,17- pentaenoyloxy)benzene. "AND

Example 27 1,4-di(2,72,2-octadeca-6,9,12-trienyl)-butane-1,4-disat. so (Diether of SGA alcohol with succinic acid) Ge)

A solution of 1,8-diazabicycloi|5.4.0)undec-7-ene (0.54 mL) in dry tetrahydrofuran (10 mL) was added dropwise to a cooled (07) solution of 7,2,2-octadeca-6,9 ,12-trienol (1 g) and succinic anhydride -

35 (0.36 g) in dry tetrahydrofuran (20 ml). At the end of the reaction, which was determined by chromatography, the mixture was diluted with diethyl ether and washed with dilute hydrochloric acid, water and brine. The organic layer was dried, concentrated and directly used for the second part of the reaction.

Part 2: "

A solution of 1,3-dicyclohexylcarbodiimide (0.83 g) and 4-(M,M-dimethylamino)pyridine (0.55 g) in methylene chloride (20 mL) was added to a solution of 1-(72,727,2-octadeca -6,9,12-trienyl)-butane-1,4-disate (1.32 g) and 7,7,72-octadeca-b,9,12-trienol (0.98 g) in methylene chloride (40 ml). After the end of the reaction, confirmed by "" chromatography, the mixture was diluted with hexane, filtered, concentrated, and 1,4-di(2,72,2-octadeca-6,9,12-trienyl)-butane-1,4-disate was isolated in in the form of a pale yellow oily substance.

Example 28

Gee! 2-(2-methyl-5-nitroimidazolyl)ethyl,2,2-octadeca-6,9,12-trienoate (Ester of metronidazole with SI A) - Method A: o To a suspension of metronidazole (206 g) in anhydrous acetonitrile ( 2,2,2-octadeca-6,9,12-trienoyl chloride (373 g) was added to anhydrous pyridine (107 mL) at room temperature under nitrogen with stirring over a period of 30 minutes. Shortly after the hydrochloric anhydride was added, a clear solution was formed, and

The stirring was continued for the next 2 hours. The mixture was allowed to settle overnight, after which the solvent was removed by mass (507C/20 mm Hg). Ethyl acetate (1000 ml) was added to the residue (precipitate), then all solid particles in the precipitate were filtered. The ethyl acetate solution was then washed with 5B saline solution, 2M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and finally again with saline solution. After drying (sodium sulfate), the solvent was removed to yield a tan oily substance. This material was processed on a dry column chromatography to give 2-(2-methyl-5-nitroimidazolyl)ethyl,2,2-octadeca-6b,9,12-trienoate as a pale yellow, insoluble oil. in Method:

Metronidazole (1.9 g) was suspended in toluene (30 mL); after that, the suspension was heated while stirring with reverse cooling using the head (ОХОеап апа е(агк)) for 20 minutes in order to completely remove water. 7,2,2-octadeca- 6,9,12-trienoyl chloride (2.96 g). The solution was heated under reflux for the next 2 h with stirring to give a dark colored mixture. After cooling, the mixture was again subjected to dry column chromatography to give was finally obtained

2-(2-methyl-5-nitroimidazolyl)ethyl-2,2,2-octadeca-6,9,12-trienoate in the form of a pale yellow insoluble oily substance.

Example 29 2-(2-methyl-5-nitroimidazolyl)ethyl-2,2-octadeca-9,12-dienoate (Metronidazole ester with LC)

4-(M,M-dimethylamino)pyridine, 1,3-dicyclohexylcarbodiimide (2.2 g) and linoleic acid (2.8 g) were successively added to a suspension of metronidazole (1.9 g) in dry dichloromethane (20 ml). The mixture was stirred at room temperature overnight. 2M Hydrochloric 7/0 Acid (20 mL) was added to the reaction mixture and stirring was continued. After filtration, the organic layer was separated, washed with 50906 saturated saline solution and finally washed with saturated aqueous sodium bicarbonate solution.

The dichloromethane solution was dried (sodium sulfate) and evaporated in hot water (307 C/20 mm Hg). Gasoline (boiling point 30-60", 20 ml) was added to the resulting residue, after which the mixture was left to settle at room temperature for 2 hours, creating conditions for the precipitation of residual urea (urea), it was removed by filtration, after which the filtrate was treated on a dry column to give 2-(2-methyl-5-nitroimidazolyl)ethyl-27,2-octadeca-9,12-dienoate as a pale yellow insoluble oily substance.

Example 30 2-(2-methyl-5-nitroimidazoloyl)ethyl-2,7,2-eicose-8,11,14-trienoate. (Ester of metronidazole with AXIS A)

In a similar way, but Kk! by replacing linoleic acid with an appropriate volume of 7,7,72-eicose-8,11,14-trienoic acid, 2-(2-methyl-5-nitroimidazoloyl)ethyl-27,7,-eicose-8,11,14 is produced -trienoate

Example 31 2-(2-methyl-5-nitroimidazoloyl)ethyl-2,7,2,7,7,72-DdoCkOoZa-4,7,10,13,16,19-hexaenoate. (Complex diester of metronidazole with ONA) and)

2-(2-methyl-5-nitroimidazoloyl)ethyl-2 ,7,2,7,7,72-DdoCkOoZa-4,7,10,13,16,19-hexaenoate. Example 32 4-I3-(2-(trifluoromethyl)10H-phenothiazine-10-yl)-1-piperazineethyl-27,2,2-octadeca-6,9,12-trienoate.so (Fluphenazine diester with SI A) co

In a similar way, but with the replacement of metronidazole with the corresponding volume of the free base 4-IZ-(2-trifluoromethyl)10H-phenothiazin-10-yl|-1-piperazineethanol (fluphenazine), and linoleic acid - (587 with the corresponding volume of CA , is made from 4-13-(2-(trifluoromethyl)10H-phenothiazine-10-yl)-1-piperazineethyl-27,2,2-octadeca-6,9,12-trienoate.

Example 33 4,4-(bis 7,2,2-octadeca-6,9,12-trienoylamino)diphenylsulfone. (Bis-amide dapsone with SG A) "

4, 4-(bis 7,7,7-octadeca- 6,9,12-trienoylamino)diphenylsulfone from Example 34

M-methyl-3-phenyl-3|o,ooo-trifluoro-p-tolyl|propyl-2,72,2-octadeca-6,9,12-trienamide. (Fluoxetine amide with CI A)

Gee! In a similar way, but with the replacement of metronidazole with an appropriate volume of -3z M-methyl-3-phenyl-3| o. o. o. trifluoro-p-tolyl|Ipropylamine (fluoxetine), and linoleic acid - the corresponding volume of SI A, M-methyl-Z3-phenyl-Z(o,ozo-trifluoro-p-tolyl|propyl-2,2, 2-Octadeca-6,9,12-trienamide (ee) Example 35 with 50 trans-1-(72,2,2-octadeca-6,9,12-trienoylamino)-2-phenylcyclopropane (Tranylcypromine amide from SI A) iz» Trans-1-(7,72,2-octadeca) is produced in a similar way, but with the replacement of metronidazole with an appropriate amount of trans-1-amino-2-phenylcyclopropane (tranylcypromine), and linoleic acid with an appropriate amount of CA -6,9,12-trienoylamino)-2-phenylcyclopropane.

Example 36 o 6-Caminophenylacetyl)amino|-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo|3.2.0)heptane-2-carboxylic acid-2,2,2-octadeca-6,9 ,12-trienamide. eat) (Ampicillin amide with SI A)

Triethylamine (0.3 mL) was added to a stirred suspension of ampicillin (0.7 g) in anhydrous dimethylformamide (120 mL) under nitrogen. A complex solution was added to the transparent solution obtained after that

M-hydroxysuccinimide ester of 7,2,2-octadeca-6,9,12-trienoic acid (0.75 g) while maintaining the reaction temperature at 0-10". The reaction mixture was stirred at this temperature for another hour, after which it was was allowed to stand at room temperature overnight. At this stage, chromatographic analysis (THF/hexane) showed that most of the succinimide ester had reacted. Water (40 mL) was added to the chemical flask and 65 was mixed well. The compound was then neutralized and extracted with ethyl acetate. The extract was washed with water, dried (sodium sulfate) and concentrated to dryness to give a crude yellow glassy solid. Trituration in hexane afforded 6-Caminophenylacetyl)amino|-3,3-dimethyl -7-oxo-4-thia-1-azabicyclo|3.2.0)heptane-2-carboxylic acid-2,2,2-octadeca-6,9,12-trienamide in the form of a yellow powdery substance.

Example 37 7,7,7-octadeca-6b,9,12-trienyl-27,27,2-octadeca-6,9,12-trienoate. (OA ester with SI A alcohol) 1,3-dicyclohexylcarbodiimide (0.82 g) and 4-("M,M-dimethylamino)pyridine (0.48 g) in methylene chloride (5 ml) were added to a solution of 7.72 ,2-octadeca-6,9,12-trienol (0.95 g) and 7,72,2-octadeca-6,9,12-trienoic acid (1 g) in 7/0 V methylene chloride (10 ml) with stirring in a nitrogen atmosphere at room temperature. At the end of the reaction (after chromatographic confirmation), hexane was added to the reaction mixture, after which it was successively filtered and purified; column chromatography yielded 7,7,72-octadeca-6,9,12-trienyl-7,2,2-octadeca-6,9,12-trienoate as a pale yellow oily substance.

Example 38 7,7,7-octadeca-6,9,12-trienyl-7,2,72,72,2-eicose-5,8,11,14,17-pentaenoate. (Ester ERA with alcohol SI A)

The production is similar to example 37, but with the replacement of 2,2,2-octadeca-6,9,12-trienoic acid with 7,7.7.7.7-eicose-5,8,11,14,17-pentahexanoic acid.

Example 39 2-methyl-3-(7,7,7,7,72-eicose-5,8,11,14,17-pentaenoyloxy)-4-formyl-5-(2,2,72,72,2 -eicose-5,8,11,14,17-pentaene hydroxy)methyl pyridine. (diERA - complex ester of tridoxal)

Triethylamine (2.0 ml) was added to a suspension of pyridoxal hydrochloride (1.0 g) in methylene chloride (20 ml). A clear yellow solution was formed. After cooling in an ice bath, 7,7,7,7,7-eicose-5,8,11,14,17-pentaenoyl chloride (1.73 g) was obtained (the mixture was prepared by the reaction of EPA with oxalyl chloride in methylene chloride). The mixture was allowed to stand overnight under nitrogen with i) gradual heating to room temperature. After dilution in an equivalent volume of methylene chloride, the mixture was extracted with 2M hydrochloric acid (20 ml), washed with water (3 x 20 ml), dried and concentrated. After purification and isolation by means of single chromatography (ethyl acetate/hexane), 2-methyl-3-7,7,7,7,72-eicose-5,8,11,14,17-pentaenoyloxy- 4-formyl-5-(2,7,2,7,2-eicose-5,8,11,14,17-pentaenoyloxae)methylpyridine in the form of a transparent oily substance. co

Example 40 2-methyl-3-hydroxy-4-formyl-5-(2,72,2-octadeca-6,9,12-trienoyloxy)methylpyridine. -- (Complex SI A-ester of pyridoxal) "o

A solution of (7,2,2-octadeca-6,9,12-trienoyl chloride (800 mg, 2.7 mmol) in methylene chloride (10 mL) was added dropwise to a mixture of pyridoxal hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol) and 4-(M,M-dimethylamino)pyridine (several mg, in the volume of the catalyst) in methylene chloride (20 ml) at 0"C in nitrogen. After the completion of the reaction, confirmed by chromatography, the mixture was concentrated, purified and using "

Column chromatography (ethyl acetate/hexane) isolated 2-methyl-3-hydroxy-4-formyl-5-(27,7,2-octadeca-6,9,12-trienoyloxy)methylpyridine as a colorless oily substance, which later gradually became cold. from Example 41 2-methyl-3-hydroxy-4,5-di(7,72,2-octadeca-6,9,12-trienoyloxy)methyl pyridine. (Bis SI A-ester of pyridoxine)

A solution of 7,2,2-octadeca-6,9,12-trienoyl chloride (650 mg, 2.2 mmol) in methylene chloride (10 mL) was slowly added dropwise to a mixture of pyridoxine hydrochloride (206 mg, 1 mmol), triethylamine (0.7 ml, 5 mmol) and - 4-(«M,M-dimethylamino)pyridine (several mg, in the volume of the catalyst) in methylene chloride (20 ml) at a temperature of 07C

Go! in a nitrogen atmosphere. After completion, confirmed by chromatography (4p), the mixture was concentrated, and 2-methyl-3-hydroxy-4,5-di(7,2,2-octadeca-6,9,12-trienoyloxy )methylpyridine in the form of a colorless oily substance.

Example 42 1-6-2-(2-methyl-5-nitroimidazoloyl)ethyl)-4-(7,72,2-octadeca-6,9,12-trienyl)butane-1,4-dioate. (Complex diester of metrongdazole and OA alcohol with succinic acid)

A solution of 1,3-dicyclohexylcarbodiimide (780 g, 3.8 mmol) and 4-(M,M-dimethylamino)pyridine (530 mg, 4.3 mmol)

F) in methylene chloride (15 ml) was added with stirring to a solution of succinate ester I A-alcohol ka (1.25 g, 3.3 mmol) (prepared similarly to example 27, part 1) and metronidazole (620 mg, 3, 6 mmol) in methylene chloride (30 mL) at room temperature under nitrogen After completion of the reaction, confirmed by X-chromatography, the mixture was diluted with hexane, filtered, concentrated and purified by flash chromatography (ethyl acetate/hexane). Product fractions were isolated and concentrated; (1-(2-(2-methyl-5-nitroimidazoloyl)ethyl)-4-(2,7,2-octadeca-6,9,12-trienyl)-1,4-butanedisate was obtained as a colorless oily substances

Example 43 65 Trans-1-(7,72,2-octadeca-6,9,12-trienyloxycarbonyl butyloxyamino)-2-phenyl cyclopropane. (succinic acid, complex alcohol ether 1-O1 A, 4-tranylcypromine amide)

A solution of 1,3-dicyclohexylcarbodiimide (315 mg, 1.52 mmol) and 4-(N,M-dimethylamino)pyridine (210 mg, 1.72 mmol) in methylene chloride (10 mL) was added with stirring to a solution of the succinate ester

SI A-alcohol (500 mg, 1.32 mmol) (prepared analogously to example 27, part 1) and tranylcypramine (225 mg, 1.32 mmol) in methylene chloride (20 mL) at room temperature under a nitrogen atmosphere. After completion of the reaction, confirmed chromatography, the mixture was diluted with hexane, filtered, concentrated, and purified by flash chromatography (ethyl acetate/hexane). The product fractions were collected and concentrated to yield trans-1-(7,72,2-octadeca-6,9,12 -trienyloxycarbonyl butyloxyamino)-2-phenylcyclopropane in the form of a colorless oily substance. 70 Example 44 (1)-2,5,7,8-tetramethyl-2-(4,8,12-trimethyldecyl)-6-chromanyl-2, 2,2-octadeca-6,9,12-trienoate (Complex SI A-ester of o-tocopherol). 7,7,7-:Octadeca-6,9,12-trienoyl chloride (2.96, 10 mmol) by was added dropwise with stirring for 2-3 minutes to a solution of (-)-A-tocopherol (4.3 g, 10 mmol) and pyridine (0.885 ml, 11 mmol) in methylene chloride (35 75 ml) in nitrogen at -57 C. After that the reaction mixture was left under stirring for no h, with gradual warming to room temperature. The analysis of HTSH showed that the reaction was almost completely finished. The mixture was washed with water (10 mL), 2 mM hydrochloric (hydrochloric) acid (10 mL in 100 mL water), and a second time with water (4 x 100 mL).

The organic layer was dried (sodium sulfate) and concentrated. Further treatment using a chromatographic column (ether/hexane) yielded (t)-2,5,7,8-tetramethyl-2-(4,8,12'i-trimethyldecyl)-6b-chromanyl-2,27 ,2-octadeca-6,9,12-trienoate in the form of a pale yellow oily substance.

Example 45

Androst-5-en-17-one-3-(7,7,7,7,7,72-DdOoCOZa-4,7,10,13,16,19-hexaenoate). (Complex ONA-ester of dehydroepiandrosterone) Ha

727,2,72,2,72,2-dOKOZA-4,7,10,13,16,19 was added to a cooled (07C) mixture of dehydroepiandrosterone (1 g) and triethylamine (1 ml) in methylene chloride (20 ml) -hexaenoyl chloride (1.33 g) (prepared by reaction of ONA with oxalyl chloride in methylene chloride). The mixture was stirred overnight, gradually warming to room temperature. After that, it was diluted with methylene chloride (20 ml), extracted with 2 mM hydrochloric acid (20 ml), washed with water (2 x 20 ml), dried and concentrated. After processing on a chromatographic column "I (ethyl acetate/hexane), dehydroepiandrost-5-en-17-one-3-(7,2,2,7,7,72-DdocoZza-4,7,10,13) was obtained at the output. 16,19-hexaenoate) in the form of a transparent oily substance. ee)

Example 46 7,7,7-octadeca-6,9,12-trienyl-(2(7,7,2-octadeca-6,9,12-trienyloxy)acetate). -- (Complex ester of SGA and si A-alcohol with glycolic acid) Ge)

Part 1:

A solution of chloroacetyl chloride (0.4 mL, 5 mmol) in methylene chloride (10 mL) was added dropwise to a solution of 7,7,72-octadeca-6b,9,12-trienol (1 g, 3.8 mmol) and triethylamine (1 .4 ml, 10 mmol) in methylene chloride (20 ml) at "0"C. The course of the reaction was monitored with the help of a TTS. After 3 hours, the reaction took place for the main volume of reagents, but not completely. A few additional drops of chloroacetyl chloride were added. c Analyzing by HTS for 5 minutes showed that the reaction had already taken place completely. The obtained mixture was washed with water (2 x 50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated. "» After that, for the purpose of azeotropic Toluene (50 ml) was added to remove the final smallest impurities of water.

Thus, the complex chloroacetyl ether SI A was obtained in the form of a dark brown oily substance, which was then used without any additional purification.

He») Part 2: -3z A mixture of 27,2,2-octadeca-6,9,12-trienoic acid (700 mg, 2.5 mmol) and cesium carbonate (410 mg, 1.25 mmol) was stirred vigorously in methanol until the mixture turns into a clear solution. Next, this solution (oo) was concentrated and kept at 40"C under vacuum for 1 hour. Cesium salt CA was obtained at the output, which was then used without additional purification.

Me Part 3: "z" To a flask containing the cesium salt CA prepared according to part 2 was added the complex chloroacetyl ester of the alcohol OGA (Part 1) (500 mg, 1.5 mmol) and dry dimethylformamide (15 mL). The reaction mixture was stirred under a nitrogen atmosphere at room temperature. After 90 minutes, the analysis of HTSH showed that the reaction had taken place completely. The resulting mixture was then extracted with hexane (2 x 40 mL), and the hexane extract was washed with brine (2 x 50 mL) and water (50 mL), dried (sodium sulfate) and concentrated; obtained at the exit

F, 7,7,7-octadeca-6,9,12-trienyl-(2(7,2,2-octadeca-6,9,12-trienyloxy)acetate) in the form of a colorless oily substance.

Example 47 60 Hydrocortisone-21-(7,72,2-octadeca-6,9,12-trienoate). (SI A-ester of hydrocortisone)

A solution of 2,2,2-octadeca-6,9,12-trienoyl chloride (450 mg, 1.52 mmol) in methylene chloride (10 mL) was slowly added dropwise to a mixture of hydrocortisone (500 mg, 1.38 mmol), triethylamine (420 ml, 3 mmol) and 4-(M,M-dimethylamino)pyridine (several mg, in the volume of the catalyst) in methylene chloride (20 ml) at 0"C in a nitrogen 65 atmosphere. After 4 hours, HTS analysis showed that the reaction was complete The mixture was concentrated and chromatographed (ethyl acetate/hexane) to give hydrocortisone-21-(2,72,2-octadeca-6,9,12-trienoate)

in the form of a colorless oily substance.

Example 48 7,7,72-octadeca-6,9,12-trienyl-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl indole-3-acetyloxy)acetate)

Diester of indomethacin and SI A-alcohol with glycolic acid.

Part 1:

A mixture of indomethacin (895 mg, 2.5 mmol) and cesium carbonate (410 mg, 1.25 mmol) was stirred vigorously in methanol until a clear solution was formed. Next, the solution was concentrated and kept at 40"C under high vacuum for 1 hour. 70 The cesium salt of indomethacin was obtained as a bright yellow solid.

Part 2:

To a flask containing the indomethacin cesium salt prepared according to part 1 of this reaction was added the complex chloroacetyl ester of SI A alcohol (prepared according to Example 46, part 1) (500 mg, 1.5 mmol) and dry dimethylformamide (15 ml ). The reaction mixture was stirred under nitrogen at room temperature, and the progress of the reaction was monitored by HTSh. After settling overnight in the refrigerator, chromatographic analysis confirmed the completion of the reaction. The mixture was then partitioned between water (50 mL) and ethyl acetate (50 mL). A few milliliters of salt solution were added in order to separate the emulsion. The ethyl acetate layer was washed with water (3 x 50 mL), dried (sodium sulfate), filtered through a pad of silica filter material, and concentrated; 7,7,72-octadeca-6,9,12-trienyl-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl indole-3-acetyloxy)acetate) was obtained as a bright yellow oily substance.

Example 49 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(4-phenylbutanoyloxy)propane. (Complex diester of 4-phenylbutanoic acid and SA with 1,3-propane diol). high school

A solution of 1,3-dicyclohexylcarbodiimide (710 mg, 3.45 mmol) and 4-(M,M-dimethylamino)pyridine (475 mg, 3.9

MMmol) in methylene chloride (per ml) was added to a solution of i) 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 3 mmol) and 4-phenylbutanoic acid (520 mg, 3.15 mmol) in methylene chloride (15 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere until the final completion of the reaction, confirmed by HTS. Then the mixture was filtered, "Mr

It was concentrated and 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(4-phenylbutanoyloxy)propane was obtained by column chromatography. co

Example 50 with 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(phenylacetoxy)propane. (Ester of phenylacetic acid and 01 A with 1,3-propane-diol) --

Analogously to example 49, but replacing 4-phenylbutanoic acid with phenylacetic acid (430 mg, 3.15 mmol) 1-(7,72,2-octadeca-6,9,12-trienoyloxy)-3-(phenylacetoxy) was prepared )propane.

Example 51 1-(2,2,2-octadeca-6,9,12-trienoyloxy)-3-(trans-cinnamoyloxy)propane. (Complex diester of trans-cinnamic|Ycinnamic - translation) acid and 01 A with 1,3-propane-diol) «

1-(7,72,2-octadeca-6,9,12-trienoyloxy)-3 -(trans-cinnamoyloxy)propane.

The claims of the invention do not relate to compounds containing niacin, which is the subject of a separate application, which was given by the same number.

Claims (18)

45 Formula of the invention - 1. Compounds that have a chemical structure linked by 1,3-propanediol: со Сов": o 50 iz» CH, 2 сно? o where B! includes an acyl group or a fatty alcohol group that is a derivative of a fatty acid with 12-30 carbon atoms, preferably with 16-30 carbon atoms, with two or more cis- or trans-double bonds, and B is hydrogen or includes an acyl group or a fatty alcohol group, the same as B or another, or is any other nutrient, drug, or other biologically active substance other than a niacin residue. 2. Compound according to claim 1, where between B! and/or B2 and the 1,3-propanediol residue includes a phosphate, succinate or other difunctional acid group, especially when BC? is a nutrient, drug or other biologically active substance that includes a functional hydroxy or amino group. C. A compound according to any one of claims 1 or 2, wherein the fatty acid is an essential fatty acid of the n-6 or n-3 series, or oleic acid, or columbic acid, or parinaric acid, or conjugated linoleic acid. 4. The compound according to item C, where the fatty acid is gamma-linolenic acid, digomo-gamma-linolenic acid, arachidonic acid, adrenoic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid of the p-3 series, docosahexaenoic acid or conjugated linoleic acid. 5. A compound according to any one of claims 1, 2, C or 4, where the BO is a medicinal substance or other active substance that must penetrate through lipid membranes in the body in order to exert its activity either when entering that cell, either during movement inside the cell where it is supposed to act, or when penetrating through the skin, blood-brain, or other barrier. 70 6. The compound according to any of claim 1, 2, C or 4, where, regardless of the type of penetration through lipid membranes, K 2 is a medicinal substance, vitamin, amino acid, antioxidant or other active substance that should provide an additive, complementary or synergistic to the action of 7. The compound according to claim 71, which includes two fatty acids, one of which is gamma-linolenic (IA) or digomo-gamma-linolenic (OCI A) acid, and the second is gamma-linolenic (CA), digomo-gamma-linolenic "(OBO A), stearidonic (ZA), eicosapentaenoic (ERA), docosahexaenoic (ONA), conjugated linoleic (si A) or columbic (CA) acid. 8. The compound according to claim 1, which includes two fatty acids, one of which is arachidonic acid (AA), and the second is arachidonic acid (AA), gamma-linolenic (CA), docosahexaenoic (ONA), digomo-gamma-linolenic (OCI A) or eicosapentaenoic (EPA) acid. 9. The compound according to claim 1, which includes two fatty acids, one of which is eicosapentaenoic acid (EPA), and the other is eicosapentaenoic (EPA) or docosahexaenoic (ONA) acid. 10. The compound according to claim 1, where one position is occupied by a fatty acid from the series SGA, OSI A, AA, ZA, SI A, ERA or ONA, and the second position is occupied by a substance selected from the list below, the chemical structure of which is such that it can be connected to 1,3-propanediol through a free carboxyl, alcohol or amino group: c (a) tryptophan; o (b) phenylalanine; (c) arginine; (d) carnitine or its derivatives; (e) any other amino acid or its derivatives, or aminolevulinic acid or its derivatives; "(e) adenylosuccinate or its derivatives; co (is) aspirin, salicylic acid, indomethacin, ibuprofen or any other non-steroidal anti-inflammatory drug; c (g) any antibiotic, especially tetracycline, clindamycin, minocycline, chlortetracycline and erythromycin; “- (3) any antimalarial or antiprotozoal drug, especially chloroquine, mepacrine, quinacrine, and mefloquine; (Se) (y) any antifungal medicinal substance, especially metronidazole and antifungal imidazoles, nitroimidazoles and amphotericin; (i) any anti-inflammatory steroid, especially hydrocortisone, betamethasone, beclomethasone, and budesonide; "(j) any gonadal steroid, especially estrogens, progestogens, and androgens; (u any adrenosteroid, especially dehydroepiandrosterone; - c (l) any retinoid, especially tretinoin and isotretinoin; h (m) any anticancer drug; n (n) any antipsychotic drug; (o) any antidepressant; (n) any drug for the treatment of anxiety; (2) (p) any immunosuppressant, especially cyclosporine and tacrolimus; - (c) any proton pump inhibitor or H2 antagonist; (t ) any diuretic medicinal substance; co (u) any calcium antagonist; o 20 (f) any angiotensin-converting enzyme inhibitor or antotensin antagonist; (CO any beta-blocker; i" (C ) any antiepileptic drug, especially phenytoin, carbamazepine, valproate, ethosuximide, vigabatrin, or lamotrigine; (h) any lipid-lowering agent, especially fibrates and statins; 22 (w) any oral hypoglycemic or insulin-sensitizing drug o (sh) any bisphosphonates; (5) building any contrast agents used in radiology, in particular, compounds of diatrizoate, co-iodipamide, ioglycamates, iopansates, iophendilate, iothalamate, ioxaglate, metrizamide and their derivatives; y) any peptide or protein, including insulin, calcitomin, erythropoietin; 60 (i) any vitamin; (aa) any antioxidant; (66) any porphyrin, chlorin, or bacteriochlorin-based drugs, especially tetrakis (hydroxyphenyl) and its derivatives. 11. A composition for skin or hair care or for the treatment of skin diseases, which contains the compound according to any one of claims 1-10. 12. A food product containing a compound according to any one of claims 1-10. 13. A food product according to claim 12, which contains a compound according to claim 10, and said substance is a vitamin or an antioxidant. 14. A food supplement containing a compound according to any one of claims 1-10. 15. Food supplement according to claim 14, which contains a compound according to claim 10, and said substance is a vitamin or an antioxidant. 16. A nutritional supplement containing a compound according to any one of claims 1-10. 17. Nutritional supplement according to claim 16, which contains a compound according to claim 10, and said substance is a vitamin or an antioxidant. 70 18. Medicinal product containing a compound according to any one of claims 1-10. 6) « (ee) (ee) «- (Se) - with . and? (o) - (ee) ге» ШИ s» ime) 60 b5